Electrophysiology publications

Piccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ) proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs), but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus-the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo ("Piccolino") present at the upstream ribbon synapses of cochlear inner hair cells (IHC), is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC), while eEPSC kinetics as well as miniature EPSCs (mEPSCs) remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP) of synaptic vesicles (SV), as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability, while the synapses still exhibited the reduced RRP, and the impairment in SV replenishment was exacerbated. We propose additive roles of Piccolo and Bassoon in SV replenishment which in turn influences the organization and size of the RRP, and an additional role of Bassoon in regulation of release probability.

The integration of multiple sensory modalities is a key aspect of brain function, allowing animals to take advantage of concurrent sources of information to make more accurate perceptual judgments. For many years, multisensory integration in the cerebral cortex was deemed to occur only in high-level “polysensory” association areas. However, more recent studies have suggested that cross-modal stimulation can also influence neural activity in areas traditionally considered to be unimodal. In particular, several human neuroimaging studies have reported that extrastriate areas involved in visual motion perception are also activated by auditory motion, and may integrate audio-visual motion cues. However, the exact nature and extent of the effects of auditory motion on the visual cortex have not been studied at the single neuron level. We recorded the spiking activity of neurons in the middle temporal (MT) and medial superior temporal (MST) areas of anesthetized marmoset monkeys upon presentation of unimodal stimuli (moving auditory or visual patterns), as well as bimodal stimuli (concurrent audio-visual motion). Despite robust, direction selective responses to visual motion, none of the sampled neurons responded to auditory motion stimuli. Moreover, concurrent moving auditory stimuli had no significant effect on the ability of single MT and MST neurons, or populations of simultaneously recorded neurons, to discriminate the direction of motion of visual stimuli (moving random dot patterns with varying levels of motion noise). Our findings do not support the hypothesis that direct interactions between MT, MST and areas low in the hierarchy of auditory areas underlie audiovisual motion integration.

Brain-specific link protein Bral2 represents a substantial component of perineuronal nets (PNNs) enwrapping neurons in the central nervous system. To elucidate the role of Bral2 in auditory signal processing, the hearing function in knockout Bral2-/- (KO) mice was investigated using behavioral and electrophysiological methods and compared with wild type Bral2+/+ (WT) mice. The amplitudes of the acoustic startle reflex (ASR) and the efficiency of the prepulse inhibition of ASR (PPI of ASR), produced by prepulse noise stimulus or gap in continuous noise, was similar in 2-week-old WT and KO mice. Over the 2-month postnatal period the increase of ASR amplitudes was significantly more evident in WT mice than in KO mice. The efficiency of the PPI of ASR significantly increased in the 2-month postnatal period in WT mice, whereas in KO mice the PPI efficiency did not change. Hearing thresholds in 2-month-old WT mice, based on the auditory brainstem response (ABR) recordings, were significantly lower at high frequencies than in KO mice. However, amplitudes and peak latencies of individual waves of click-evoked ABR did not differ significantly between WT and KO mice. Temporal resolution and neural adaptation were significantly better in 2-month-old WT mice than in age-matched KO mice. These results support a hypothesis that the absence of perineuronal net formation at the end of the developmental period in the KO mice results in higher hearing threshold at high frequencies and weaker temporal resolution ability in adult KO animals compared to WT mice.

Electrocortical stimulation (ECS) mapping is routinely used to identify critical language sites before resective neurosurgery. The precise locations of these sites are highly variable across patients, occurring in the frontal, temporal, and parietal lobes-it is this variability that necessitates individual patient mapping. But why these particular anatomical sites are so privileged in each patient is unknown. We hypothesized that critical language sites have greater functional connectivity with nearby cortex than sites without critical functions, since they serve as central nodes within the language network. Functional connectivity across language, motor, and cleared sites was measured in 15 patients undergoing electrocortiographic (ECoG) mapping for epilepsy surgery. Critical language sites had significantly higher connectivity than sites without critical functions (P = 0.001), and this also held for motor sites (P = 0.022). These data support the hypothesis that critical language sites are highly connected within the local cortical network, perhaps explaining why their disruption with ECS leads to transient disturbances in language function. It is our hope that improved understanding of the mechanisms of ECS will permit improved surgical planning and perhaps contribute to the understanding of normal language physiology.

Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli. Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms. Here we present new evidence that impaired development of parvalbumin (PV)-expressing inhibitory interneurons may underlie hyper-responsiveness in auditory cortex of Fmr1 KO mice via MMP-9-dependent regulation of perineuronal nets (PNNs). First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice. Second, MMP-9 levels were elevated in P12-P18 auditory cortex of Fmr1 KO mice and genetic reduction of MMP-9 to WT levels restored the formation of PNNs around PV cells. Third, in vivo single-unit recordings from auditory cortex neurons showed enhanced spontaneous and sound-driven responses in developing Fmr1 KO mice, which were normalized following genetic reduction of MMP-9. These findings indicate that elevated MMP-9 levels contribute to the development of sensory hypersensitivity by influencing formation of PNNs around PV interneurons suggesting MMP-9 as a new therapeutic target to reduce sensory deficits in FXS and potentially other autism spectrum disorders.

Throughout the visual system, different subtypes of neurons are tuned to distinct aspects of the visual scene, establishing parallel circuits. Defining the mechanisms by which such tuning arises has been a long-standing challenge for neuroscience. To investigate this, we have focused on the retina's projection to the superior colliculus (SC), where multiple visual neuron subtypes have been described. The SC receives inputs from a variety of retinal ganglion cell (RGC) subtypes; however, which RGCs drive the tuning of different SC neurons remains unclear. Here, we pursued a genetic approach that allowed us to determine the tuning properties of neurons innervated by molecularly defined subpopulations of RGCs. In homozygous Islet2-EphA3 knock-in (Isl2EA3/EA3) mice, Isl2+ and Isl2- RGCs project to non-overlapping sub-regions of the SC. Based on molecular and anatomic data, we show that significantly more Isl2- RGCs are direction-selective (DS) in comparison with Isl2+ RGCs. Targeted recordings of visual responses from each SC sub-region in Isl2EA3/EA3 mice revealed that Isl2- RGC-innervated neurons were significantly more DS than those innervated by Isl2+ RGCs. Axis-selective (AS) neurons were found in both sub-regions, though AS neurons innervated by Isl2+ RGCs were more tightly tuned. Despite this segregation, DS and AS neurons innervated by Isl2+ or Isl2- RGCs did not differ in their spatial summation or spatial frequency (SF) tuning. Further, we did not observe alterations in receptive field (RF) size or structure of SC neurons innervated by Isl2+ or Isl2- RGCs. Together, these data show that innervation by Isl2+ and Isl2- RGCs results in distinct tuning in the SC and set the stage for future studies investigating the mechanisms by which these circuits are built.

Predicting the behavior of others is a fundamental skill in primate social life. We tested the role of medial frontal cortex in the prediction of other agents’ behavior in two male macaques, using a monkey-human interactive task in which their actor-observer roles were intermixed. In every trial, the observer monitored the actor’s choice to reject it for a different one when he became the actor on the subsequent trial. In the delay period preceding the action, we identified neurons modulated by the agent’s identity, as well as a group of neurons encoding the agent’s future choice, some of which were neurons that showed differential patterns of activity between agents. The ability of these neurons to flexibly move from ‘self-oriented’ to ‘other-oriented’ representations could correspond to the “other side of the coin” of the simulative mirroring activity. Neurons that changed coding scheme, together with neurons exclusively involved in the prediction of the other agent’s choice, show a neural substrate for predicting or anticipating others’ choices beyond simulation.

Cathodal-transcranial direct current stimulation induces therapeutic effects in animal ischemia models by preventing the expansion of ischemic injury during the hyperacute phase of ischemia. However, its efficacy is limited by an accompanying decrease in cerebral blood flow. On the other hand, peripheral sensory stimulation can increase blood flow to specific brain areas resulting in rescue of neurovascular functions from ischemic damage. Therefore, the two modalities appear to complement each other to form an integrated treatment modality. Our results showed that hemodynamics was improved in a photothrombotic ischemia model, as cerebral blood volume and hemoglobin oxygen saturation (SO2) recovered to 71% and 76% of the baseline values, respectively. Furthermore, neural activities, including somatosensory-evoked potentials (110% increase), the alpha-to-delta ratio (27% increase), and the (delta+theta)/(alpha+beta) ratio (27% decrease), were also restored. Infarct volume was reduced by 50% with a 2-fold preservation in the number of neurons and a 6-fold reduction in the number of active microglia in the infarct region compared with the untreated group. Grip strength was also better preserved (28% higher) compared with the untreated group. Overall, this nonpharmacological, nonintrusive approach could be prospectively developed into a clinical treatment modality.

Rodents lick to consume fluids. The reward value of ingested fluids is likely to be encoded by neuronal activity entrained to the lick cycle. Here, we investigated relationships between licking and reward signaling by the medial frontal cortex (MFC), a key cortical region for reward-guided learning and decision-making. Multielectrode recordings of spike activity and field potentials were made in male rats as they performed an incentive contrast licking task. Rats received access to higher- and lower-value sucrose rewards over alternating 30 s periods. They learned to lick persistently when higher-value rewards were available and to suppress licking when lower-value rewards were available. Spectral analysis of spikes and fields revealed evidence for reward value being encoded by the strength of phase-locking of a 6–12 Hz theta rhythm to the rats' lick cycle. Recordings during the initial acquisition of the task found that the strength of phase-locking to the lick cycle was strengthened with experience. A modification of the task, with a temporal gap of 2 s added between reward deliveries, found that the rhythmic signals persisted during periods of dry licking, a finding that suggests the MFC encodes either the value of the currently available reward or the vigor with which rats act to consume it. Finally, we found that reversible inactivations of the MFC in the opposite hemisphere eliminated the encoding of reward information. Together, our findings establish that a 6–12 Hz theta rhythm, generated by the rodent MFC, is synchronized to rewarded actions. SIGNIFICANCE STATEMENT The cellular and behavioral mechanisms of reward signaling by the medial frontal cortex (MFC) have not been resolved. We report evidence for a 6–12 Hz theta rhythm that is generated by the MFC and synchronized with ongoing consummatory actions. Previous studies of MFC reward signaling have inferred value coding upon temporally sustained activity during the period of reward consumption. Our findings suggest that MFC activity is temporally sustained due to the consumption of the rewarding fluids, and not necessarily the abstract properties of the rewarding fluid. Two other major findings were that the MFC reward signals persist beyond the period of fluid delivery and are generated by neurons within the MFC.

Previous work has debated about the comparisons of hearing abilities faced with alterations in hearing thresholds and evoked potentials between groups following acoustic trauma- or age-related changes. This study compares envelope-following responses (EFRs) of young and aged rats when sound levels were matched according to (1) wave I amplitudes of auditory brainstem responses (ABRs) elicited by 8-kHz tones or (2) EFR amplitudes evoked by sinusoidally amplitude-modulated (SAM) tones at 100% depth. Matched wave I amplitudes across age corresponded to approximately 20-dB sound level differences. For matched wave I, no age-related differences were observed in wave V amplitudes. However, EFRs recorded in silence were enhanced with aging at 100% but not at 25% depth, consistent with enhanced central gain in aging. For matched EFRs, there were no age-related differences in EFRs of amplitude modulation (AM) depth and AM frequency processing. These results suggest novel, objective measures beyond threshold to compensate for differences in auditory nerve activation and to differentiate peripheral and central contributions of EFRs.

Background: Our group has previously shown that activation of specific facial nerve (FN) fiber populations and selective activation of facial musculature can be achieved through acute intraneural multichannel microelectrode array (MEA) implantation in the feline model. Hypothesis: Selective stimulation of facial muscles will be maintained in the setting of 1) chronic and 2) acute MEA implantation after FN injury and subsequent recovery. Methods: This study included seven cats. In three cats with normal facial function, 4-channel penetrating MEAs were implanted chronically in the FN and tested biweekly for 6 months. Electrical current pulses were delivered to each channel individually, and elicited electromyographic (EMG) voltage outputs were recorded for each of several facial muscles. For FN injury experiments, two cats received a standardized hemostat-crush injury, and two cats received a transection-reapproximation injury to the FN main trunk. These four underwent acute implantation of MEA and EMG recording in terminal experiments 4 months postinjury. Results: Stimulation through individual channels selectively activated restricted nerve populations, resulting in activation of individual muscles in cats with chronic MEA implantation and after nerve injury. Increasing stimulation current levels resulted in increasing EMG voltage responses in all patients. Nerve histology showed only minor neural tissue reaction to the implant. Conclusion: We have established in the animal model the ability of a chronically implanted MEA to selectively stimulate restricted FN fiber populations and elicit activations in specific facial muscles. Likewise, after FN injury, selective stimulation of restricted FN fiber populations and subsequent activation of discrete facial muscles can be achieved after acute MEA implantation.

Visual object information is conveyed from V1 to area TE along the ventral visual pathway with increasing receptive field (RF) sizes. The RFs of TE neurons are known to be large, but it is largely unknown how large RFs are shaped along the ventral visual pathway. In this study, we addressed this question in two aspects, static and dynamic mechanisms, by recording neural responses from macaque area TE and V4 to object stimuli presented at various locations in the visual field. As a component related to static mechanisms, we found that in area TE, but not in V4, response latency to objects presented at fovea were different from objects in periphery. As a component of the dynamic mechanisms, we examined effects of spatial attention on the RFs of TE neurons. Spatial attention did not affect response latency but modulated response magnitudes depending on attended location, shifting of the longitudinal axis of RFs toward the attended locations. In standard models of large RF formation, downstream neurons pool information from nearby RFs, and this process is repeated across the visual field and at each step along the ventral visual pathway. The present study revealed that this mechanism is not that simple: 1) different circuit mechanisms for foveal and peripheral visual fields may be situated between V4 and area TE, and 2) spatial attention dynamically changes the shape of RFs. NEW & NOTEWORTHY Receptive fields (RFs) of neurons are progressively increased along the ventral visual pathway so that an RF at the final stage, area TE, covers a large area of the visual field. We explored the mechanism and suggested involvement of parallel circuit mechanisms between V4 and TE for foveal and peripheral parts of visual field. We also found a dynamic component of RF shape formation through attentional modulation of responses in a location-dependent manner.

Interaural time differences (ITDs) conveyed by the modulated envelopes of high-frequency sounds can serve as a cue for localizing a sound source. Klein-Hennig et al. ( J Acoust Soc Am 129: 3856, 2011) demonstrated the envelope attack (the rate at which stimulus energy in the envelope increases) and the duration of the pause (the interval between successive envelope pulses) as important factors affecting sensitivity to envelope ITDs in human listeners. Modulated sounds with rapid attacks and long pauses produce the lowest ITD discrimination thresholds. The duration of the envelope’s sustained component (sustain) and the rate at which stimulus energy falls at the offset of the envelope (decay) are only minor factors. We assessed the responses of 71 single neurons, recorded from the midbrains of 15 urethane-anesthetized tri-colored guinea pigs, to envelope shapes in which the four envelope components, i.e., attack, sustain, decay, and pause, were systematically varied. We confirmed the importance of the attack and pause components in generating ITD-sensitive responses. Analysis of neural firing rates demonstrated more neurons (49/71) show ITD sensitivity in response to “damped” stimuli (fast attack and slow decay) compared with “ramped” stimuli (slow attack and fast decay) (14/71). Furthermore, the lowest threshold for the damped stimulus (91 μs) was lower by a factor of 4 than that for the temporally reversed ramped envelope shape (407 μs). The data confirm the importance of fast attacks and optimal pause durations in generating sensitivity to ITDs conveyed in the modulated envelopes of high-frequency sounds and are incompatible with models of ITD processing based on the integration of sound energy over time. NEW & NOTEWORTHY Using single-neuron electrophysiology, we show that the precise shape of a sound’s “energy envelope” is a critical factor in determining how well midbrain neurons are able to convey information about auditory spatial cues. Consistent with human behavioral performance, sounds with rapidly rising energy and relatively long intervals between energy bursts are best at conveying spatial information. The data suggest specific sound energy patterns that might best be applied to hearing devices to aid spatial listening.

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells.

We detect objects more readily if they differ from their surroundings in motion, color, or texture. This increased saliency is thought to be related to increased responses in the visual cortex. The superior colliculus is another brain area involved in vision and especially in directing gaze and attention. In this study, we show that differences in texture orientation also increase responses in the superficial layers of the superior colliculus that receive retinal and cortical input. We found that gratings evoke more neural response when surrounded by orthogonal gratings than when surrounded by parallel gratings, particularly in the awake mouse. This pop-out is not originating from the visual cortex, and silencing visual cortex increased the relative difference in response. A model shows that this can result from retinotopically matched excitation from visual cortex to the superior colliculus. We suggest that the perceptual saliency of a stimulus differing from its surround in a low-level feature like grating orientation could depend on visual processing in the superior colliculus.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1β, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

An important aspect of auditory scene analysis is auditory stream segregation—the organization of sound sequences into perceptual streams reflecting different sound sources in the environment. Several models have been proposed to account for stream segregation. According to the “population separation” (PS) model, alternating ABAB tone sequences are perceived as a single stream or as two separate streams when “A” and “B” tones activate the same or distinct frequency-tuned neuronal populations in primary auditory cortex (A1), respectively. A crucial test of the PS model is whether it can account for the observation that A and B tones are generally perceived as a single stream when presented synchronously, rather than in an alternating pattern, even if they are widely separated in frequency. Here, we tested the PS model by recording neural responses to alternating (ALT) and synchronous (SYNC) tone sequences in A1 of male macaques. Consistent with predictions of the PS model, a greater effective tonotopic separation of A and B tone responses was observed under ALT than under SYNC conditions, thus paralleling the perceptual organization of the sequences. While other models of stream segregation, such as temporal coherence, are not excluded by the present findings, we conclude that PS is sufficient to account for the perceptual organization of ALT and SYNC sequences and thus remains a viable model of auditory stream segregation. SIGNIFICANCE STATEMENT According to the population separation (PS) model of auditory stream segregation, sounds that activate the same or separate neural populations in primary auditory cortex (A1) are perceived as one or two streams, respectively. It is unclear, however, whether the PS model can account for the perception of sounds as a single stream when they are presented synchronously. Here, we tested the PS model by recording neural responses to alternating (ALT) and synchronous (SYNC) tone sequences in macaque A1. A greater effective separation of tonotopic activity patterns was observed under ALT than under SYNC conditions, thus paralleling the perceptual organization of the sequences. Based on these findings, we conclude that PS remains a plausible neurophysiological model of auditory stream segregation.

Increasing evidence suggests that cortical dynamics during wake exhibits long-range temporal correlations suitable to integrate inputs over extended periods of time to increase the signal-to-noise ratio in decision making and working memory tasks. Accordingly, sleep has been suggested as a state characterized by a breakdown of long-range correlations. However, detailed measurements of neuronal timescales that support this view have so far been lacking. Here, we show that the cortical timescales measured at the individual neuron level in freely behaving male rats change as a function of vigilance state and time awake. Although quiet wake and rapid eye movement (REM) sleep are characterized by similar, long timescales, these long timescales are abrogated in non-REM sleep. We observe that cortex dynamics exhibits rapid transitions between long-timescale states and sleep-like states governed by short timescales even during wake. This becomes particularly evident during sleep deprivation, when the interplay between these states can lead to an increasing disruption of long timescales that are restored after sleep. Experiments and modeling identify the intrusion of neuronal offline periods as a mechanism that disrupts the long timescales arising from reverberating cortical network activity. Our results provide novel mechanistic and functional links among behavioral manifestations of sleep, wake, and sleep deprivation and specific measurable changes in the network dynamics relevant for characterizing the brain's changing information-processing capabilities. They suggest a network-level function of sleep to reorganize cortical networks toward states governed by long timescales to ensure efficient information integration for the time awake. SIGNIFICANCE STATEMENT Lack of sleep deteriorates several key cognitive functions, yet the neuronal underpinnings of these deficits have remained elusive. Cognitive capabilities are generally believed to benefit from a neural circuit's ability to reliably integrate information. Persistent network activity characterized by long timescales may provide the basis for this integration in cortex. Here, we show that long-range temporal correlations indicated by slowly decaying autocorrelation functions in neuronal activity are dependent on vigilance states. Although wake and rapid eye movement (REM) sleep exhibit long timescales, these long-range correlations break down during non-REM sleep. Our findings thus suggest two distinct states in terms of timescale dynamics. During extended wake, the rapid switching to sleep-like states with short timescales can lead to an overall decline in cortical timescales.

Neuronal inhibition is crucial for temporally precise and reproducible signaling in the auditory brainstem. Previously we showed that for various synthetic stimuli, spherical bushy cell (SBC) activity in the Mongolian gerbil is rendered sparser and more reliable by subtractive inhibition (Keine et al., 2016). Here, employing environmental stimuli, we demonstrate that the inhibitory gain control becomes even more effective, keeping stimulated response rates equal to spontaneous ones. However, what are the costs of this modulation? We performed dynamic stimulus reconstructions based on neural population responses for auditory nerve (ANF) input and SBC output to assess the influence of inhibition on acoustic signal representation. Compared to ANFs, reconstructions of natural stimuli based on SBC responses were temporally more precise, but the match between acoustic and represented signal decreased. Hence, for natural sounds, inhibition at SBCs plays an even stronger role in achieving sparse and reproducible neuronal activity, while compromising general signal representation.

Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.