Bacteria use two-component systems (TCSs) to sense and respond to environmental changes. The core genome of the major human pathogen Staphylococcus aureus encodes 16 TCSs, one of which (WalRK) is essential. Here we show that S. aureus can be deprived of its complete sensorial TCS network and still survive under growth arrest conditions similarly to wild-type bacteria. Under replicating conditions, however, the WalRK system is necessary and sufficient to maintain bacterial growth, indicating that sensing through TCSs is mostly dispensable for living under constant environmental conditions. Characterization of S. aureus derivatives containing individual TCSs reveals that each TCS appears to be autonomous and self-sufficient to sense and respond to specific environmental cues, although some level of cross-regulation between non-cognate sensor-response regulator pairs occurs in vivo. This organization, if confirmed in other bacterial species, may provide a general evolutionarily mechanism for flexible bacterial adaptation to life in new niches.

Olfactory bulbs retain the ability to acquire new neurons throughout life. Unilateral olfactory deprivation during the first postnatal month in rats results in a dramatic reduction in the size of the experimental olfactory bulb. Part of this reduction is attributable to the death of neurons and glia. To examine the regenerative capacity of the juvenile olfactory bulb, we developed a technique for reversible olfactory deprivation. Reversible blockade from postnatal day 1 (P1) to P20 or P30 results in reduced bulb volume and tyrosine hydroxylase immunostaining, and decreased depth in the olfactory mucosa. In another experiment, normal stimulation was restored for varying periods of time, and experimental and control bulb volumes were measured. Recovery of bulb size occurs after 40 d of normal stimulation. Rats injected with a thymidine analog to label dividing cells during the recovery period revealed that rescue results at least in part from the addition of new neurons and glia. Thus, cells born after the return of normal levels of environmental stimulation can replace some of the neurons and glia that are lost during olfactory deprivation. This system can be used to study mechanisms that underlie neuronal regeneration in the maturing mammalian brain.

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

Experience-dependent plasticity (EDP) is essential for anatomical and functional maturation of sensory circuits during development. Although the principal synaptic and circuit mechanisms of EDP are increasingly well studied experimentally and computationally, its molecular mechanisms remain largely elusive. EDP can be readily studied in the rodent barrel cortex, where each "barrel column" preferentially represents deflections of its own principal whisker. Depriving select whiskers while sparing their neighbours introduces competition between barrel columns, ultimately leading to weakening of intracortical, translaminar (i.e., cortical layer (L)4-to-L2/3) feed-forward excitatory projections in the deprived columns. The same synapses are potentiated in the neighbouring spared columns. These experience-dependent alterations of synaptic strength are thought to underlie somatosensory map plasticity. We used RNA sequencing in this model system to uncover cortical-column and -layer specific changes on the transcriptome level that are induced by altered sensory experience. Column- and layer-specific barrel cortical tissues were collected from juvenile mice with all whiskers intact and mice that received 11-12 days of long whisker (C-row) deprivation before high-quality RNA was purified and sequenced. The current dataset entails an average of 50 million paired-end reads per sample, 75 base pairs in length. On average, 90.15% of reads could be uniquely mapped to the mm10 reference mouse genome. The current data reveal the transcriptional changes in gene expression in the barrel cortex upon altered sensory experience in juvenile mice and will help to molecularly map the mechanisms of cortical plasticity.

Experience-dependent plasticity (EDP) powerfully shapes neural circuits by inducing long-lasting molecular changes in the brain. Molecular mechanisms of EDP have been traditionally studied by identifying single or small subsets of targets along the biochemical pathways that link synaptic receptors to nuclear processes. Recent technological advances in large-scale analysis of gene transcription and translation now allow systematic observation of thousands of molecules simultaneously. Here we employed label-free quantitative mass spectrometry to address experience-dependent changes in the proteome after sensory deprivation of the primary somatosensory cortex. Cortical column- and layer-specific tissue samples were collected from control animals, with all whiskers intact, and animals whose C-row whiskers were bilaterally plucked for 11-14 days. Thirty-three samples from cortical layers (L) 2/3 and L4 spanning across control, deprived, and first- and second-order spared columns yielded at least 10 000 peptides mapping to ∼5000 protein groups. Of these, 4676 were identified with high confidence, and >3000 were found in all samples. This comprehensive database provides a snapshot of the proteome after whisker deprivation, a protocol that has been widely used to unravel the synaptic, cellular, and network mechanisms of EDP. Complementing the recently made available transcriptome for identical experimental conditions (see the accompanying article by Kole et al.), the database can be used to (i) mine novel targets whose translation is modulated by sensory organ use, (ii) cross-validate experimental protocols from the same developmental time point, and (iii) statistically map the molecular pathways of cortical plasticity at a columnar and laminar resolution.

Individuals with congenital sensory deprivation usually demonstrate altered brain morphology in areas associated with early processing of the absent sense. Here, we aimed to establish whether this also applies to individuals born without a sense of smell (congenital anosmia) by comparing cerebral morphology between 33 individuals with isolated congenital anosmia and matched controls. We detected no morphological alterations in the primary olfactory (piriform) cortex. However, individuals with anosmia demonstrated gray matter volume atrophy in bilateral olfactory sulci, explained by decreased cortical area, curvature, and sulcus depth. They further demonstrated increased gray matter volume and cortical thickness in the medial orbital gyri; regions closely associated with olfactory processing, sensory integration, and value-coding. Our results suggest that a lifelong absence of sensory input does not necessarily lead to morphological alterations in primary sensory cortex and extend previous findings with divergent morphological alterations in bilateral orbitofrontal cortex, indicating influences of different developmental processes.

The circadian system, which is essential for the alignment of sleep/wake cycles, modulates adult neurogenesis. The olfactory epithelium (OE) has the ability to generate new neurons throughout life. Loss of olfactory sensory neurons (OSNs) as a result of injury to the OE triggers the generation of new OSNs, which are incorporated into olfactory circuits to restore olfactory sensory perception. This regenerative potential means that it is likely that the OE is substantially affected by sleep deprivation (SD), although how this may occur remains unclear. The aim of this study is to address how SD affects the process of OSN regeneration following OE injury. Mice were subjected to SD for 2 weeks, which induced changes in circadian activity. This condition resulted in decreased activity during the night-time and increased activity during the daytime, and induced no histological changes in the OE. However, when subjected to SD during the regeneration process after OE injury, a significant decrease in the number of mature OSNs in the dorsomedial area of the OE, which is the only area containing neurons expressing NQO1 (quinone dehydrogenase 1), was observed compared to the NQO1-negative OE. Furthermore, a significant decrease in proliferating basal cells was observed in the NQO1-positive OE compared to the NQO1-negative OE, but no increase in apoptotic OSNs was observed. These results indicate that SD accompanied by disturbed circadian activity could induce structurally negative effects on OSN regeneration, preferentially in the dorsomedial area of the OE, and that this area-specific regeneration delay might involve the biological activity of NQO1.

The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.SIGNIFICANCE STATEMENT Successful transmission of information from the olfactory bulb (OB) to piriform cortex through the lateral olfactory tract (LOT) relies on synchronized arrival of action potentials (APs). The coincident arrival of APs is dependent on reliable generation of APs in the axon initial segment (AIS) and fast conduction mediated by axon myelination. Here, we studied changes in mitral cell (MC) firing and AIS structure as well as changes in myelination of the LOT on unilateral olfactory deprivation in the adult mouse. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to reduced sensory input. Our work demonstrates a previously unstudied mechanism of plasticity in the olfactory system.

In most everyday situations sensorimotor processes are quite complex because situations often require to carry out several actions in a specific temporal order; i.e. one has to cascade different actions. While it is known that changes to stimuli affect action cascading mechanisms, it is unknown whether action cascading changes when sensory stimuli are not manipulated, but the neural architecture to process these stimuli is altered. In the current study we test this hypothesis using prelingually deaf subjects as a model to answer this question. We use a system neurophysiological approach using event-related potentials (ERPs) and source localization techniques. We show that prelingually deaf subjects show improvements in action cascading. However, this improvement is most likely not due to changes at the perceptual (P1-ERP) and attentional processing level (N1-ERP), but due to changes at the response selection level (P3-ERP). It seems that the temporo-parietal junction (TPJ) is important for these effects to occur, because the TPJ comprises overlapping networks important for the processing of sensory information and the selection of responses. Sensory deprivation thus affects cognitive processes downstream of sensory processing and only these seem to be important for behavioral improvements in situations requiring complex sensorimotor processes and action cascading.

Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+)-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.

The role of monoaminergic neuromodulators in the reorganization of cortical topography following limited sensory deprivation in the adult cat was investigated. The total concentrations of dopamine, noradrenaline, serotonin and their major metabolites were measured in the visual cortex of both normal control and experimental animals using microbore high-performance liquid chromatography coupled with electrochemical detection. The experimental animals were subjected to a binocular retinal lesion corresponding to the central 10 degrees of vision and killed two weeks post-lesion. The sensory deprivation was confirmed in area 17 by measuring immediate-early gene zif-268 messenger RNA expression. Following the retinal lesion, the total concentrations of noradrenaline and dopamine were significantly higher in the non-deprived cortex of retinal lesion cats than in the deprived cortex of retinal lesion cats and the cortex of normal animals. This pattern follows the release of the excitatory neurotransmitter glutamate under the same conditions. Serotonin levels were significantly lower in the deprived cortex, and its metabolite 5-hydroxyindole-3-acetic acid was significantly higher in the non-deprived cortex than in deprived cortex and normal cortex. From these results, we suggest that the modulation of noradrenaline, dopamine and serotonin is regulated by visual afferent activity.

Experience regulates synapse formation and function across sensory circuits. How inhibitory synapses in the mammalian retina are sculpted by visual cues remains unclear. By use of a sensory deprivation paradigm, we find that visual cues regulate maturation of two GABA synapse types (GABAA and GABAC receptor synapses), localized across the axon terminals of rod bipolar cells (RBCs)-second-order retinal neurons integral to the night-vision circuit. Lack of visual cues causes GABAA synapses at RBC terminals to retain an immature receptor configuration with slower response profiles and prevents receptor recruitment at GABAC synapses. Additionally, the organizing protein for both these GABA synapses, LRRTM4, is not clustered at dark-reared RBC synapses. Ultrastructurally, the total number of ribbon-output/inhibitory-input synapses across RBC terminals remains unaltered by sensory deprivation, although ribbon synapse output sites are misarranged when the circuit develops without visual cues. Intrinsic electrophysiological properties of RBCs and expression of chloride transporters across RBC terminals are additionally altered by sensory deprivation. Introduction to normal 12-h light-dark housing conditions facilitates maturation of dark-reared RBC GABA synapses and restoration of intrinsic RBC properties, unveiling a new element of light-dependent retinal cellular and synaptic plasticity.

Can alterations in experience trigger different plastic modifications in neuronal structure and function, and if so, how do they integrate at the cellular level? To address this question, we interrogated circuitry in the mouse olfactory bulb responsible for the earliest steps in odor processing. We induced experience-dependent plasticity in mice of either sex by blocking one nostril for one day, a minimally invasive manipulation that leaves the sensory organ undamaged and is akin to the natural transient blockage suffered during common mild rhinal infections. We found that such brief sensory deprivation produced structural and functional plasticity in one highly specialized bulbar cell type: axon-bearing dopaminergic neurons in the glomerular layer. After 24 h naris occlusion, the axon initial segment (AIS) in bulbar dopaminergic neurons became significantly shorter, a structural modification that was also associated with a decrease in intrinsic excitability. These effects were specific to the AIS-positive dopaminergic subpopulation because no experience-dependent alterations in intrinsic excitability were observed in AIS-negative dopaminergic cells. Moreover, 24 h naris occlusion produced no structural changes at the AIS of bulbar excitatory neurons, mitral/tufted and external tufted cells, nor did it alter their intrinsic excitability. By targeting excitability in one specialized dopaminergic subpopulation, experience-dependent plasticity in early olfactory networks might act to fine-tune sensory processing in the face of continually fluctuating inputs.SIGNIFICANCE STATEMENT Sensory networks need to be plastic so they can adapt to changes in incoming stimuli. To see how cells in mouse olfactory circuits can change in response to sensory challenges, we blocked a nostril for just one day, a naturally relevant manipulation akin to the deprivation that occurs with a mild cold. We found that this brief deprivation induces forms of axonal and intrinsic functional plasticity in one specific olfactory bulb cell subtype: axon-bearing dopaminergic interneurons. In contrast, intrinsic properties of axon-lacking bulbar dopaminergic neurons and neighboring excitatory neurons remained unchanged. Within the same sensory circuits, specific cell types can therefore make distinct plastic changes in response to an ever-changing external landscape.

The olfactory bulb (OB) is a highly plastic structure that can change organizational networks depending on environmental inputs in adult mammals. Particularly, in rodents, adult neurogenesis underlies plastic changes in the OB circuitry by continuously adding new interneurons to the network. We addressed the question of whether microglia, the immune cells of the brain, were involved in pruning OB neurons. Using lentiviral labeling of neurons in neonatal or adult mice and confocal analysis, we showed that microglia engulfed parts of neonatal-born and adult-born neurons in the healthy OB. We demonstrated that OB deafferentation by Dichlobenil administration induced sensory deprivation. It also increased phagocytosis of adult-born, but not neonatal-born neurons, by activated microglia. Conversely, intranasal lipopolysaccharide administration induced activation of microglia but changed neither adult neurogenesis nor olfaction. Our data reveal that steady-state microglia eliminate adult-born neurons and their synapses in both healthy and sensory deprived OBs, thereby adapting neuronal connections to the sensory experience.

Diverse interneuron subtypes shape sensory processing in mature cortical circuits. During development, sensory deprivation evokes powerful synaptic plasticity that alters circuitry, but how different inhibitory subtypes modulate circuit dynamics in response to this plasticity remains unclear. We investigate how deprivation-induced synaptic changes affect excitatory and inhibitory firing rates in a microcircuit model of the sensory cortex with multiple interneuron subtypes. We find that with a single interneuron subtype (parvalbumin-expressing [PV]), excitatory and inhibitory firing rates can only be comodulated-increased or decreased together. To explain the experimentally observed independent modulation, whereby one firing rate increases and the other decreases, requires strong feedback from a second interneuron subtype (somatostatin-expressing [SST]). Our model applies to the visual and somatosensory cortex, suggesting a general mechanism across sensory cortices. Therefore, we provide a mechanistic explanation for the differential role of interneuron subtypes in regulating firing rates, contributing to the already diverse roles they serve in the cortex.

Control of locomotion involves the interplay of sensory signals and motor commands. Sensory information is essential for adjusting locomotion in response to environmental changes. A previous study using mathematical modelling of lamprey swimming has shown that, in the absence of sensory feedback, increasing fluid viscosity constrains swimming kinematics, limiting tail amplitude and body wavelength, resulting in decreased swimming speed. In contrast, previous experiments with Polypterus senegalus reported increased magnitude swimming kinematics (increased body curvature, body wave speed and frequency, and pectoral fin frequency) in high viscosity water suggesting that sensory information is used to adjust swimming form. It is not known what sensory systems are providing the necessary information to respond to these environmental changes. We tested the hypothesis that lateral line and visual input are responsible for the sensory-driven increase in swimming kinematics in response to experimentally increased fluid viscosity. The kinematics of five P. senegalus were recorded in two different viscosities of water while removing lateral line and visual sensory feedback. Unlike the mathematical model devoid of sensory feedback, P. senegalus with lateral line and/or visual senses removed did not reduce the magnitude of swimming kinematic variables, suggesting that additional sensory feedback mechanisms are present in these fish to help overcome increased fluid viscosity. Increases in swimming speed when both lateral line and visual sensory feedback were removed suggest that lateral line and visual information may be used to regulate swimming speed in P. senegalus, possibly using an internal model of predictions to adjust swimming form.

Cortical areas have the capacity of large-scale reorganization following sensory deafferentation. However, it remains unclear whether this phenomenon is a unique process that homogeneously affects the entire deprived cortical region or whether it is susceptible to changes depending on neuronal networks across distinct cortical layers. Here, we studied how the local circuitry within each layer of the deafferented cortex forms the basis for neuroplastic changes after immediate thoracic spinal cord injury (SCI) in anaesthetized rats. In vivo electrophysiological recordings from deafferented hindlimb somatosensory cortex showed that SCI induces layer-specific changes mediating evoked and spontaneous activity. In supragranular layer 2/3, SCI increased gamma oscillations and the ability of these neurons to initiate up-states during spontaneous activity, suggesting an altered corticocortical network and/or intrinsic properties that may serve to maintain the excitability of the cortical column after deafferentation. On the other hand, SCI enhanced the infragranular layers' ability to integrate evoked sensory inputs leading to increased and faster neuronal responses. Delayed evoked response onsets were also observed in layer 5/6, suggesting alterations in thalamocortical connectivity. Altogether, our data indicate that SCI immediately modifies the local circuitry within the deafferented cortex allowing supragranular layers to better integrate spontaneous corticocortical information, thus modifying column excitability, and infragranular layers to better integrate evoked sensory inputs to preserve subcortical outputs. These layer-specific neuronal changes may guide the long-term alterations in neuronal excitability and plasticity associated with the rearrangements of somatosensory networks and the appearance of central sensory pathologies usually associated with spinal cord injury. KEY POINTS: Sensory stimulation of forelimb produces cortical evoked responses in the somatosensory hindlimb cortex in a layer-dependent manner. Spinal cord injury favours the input statistics of corticocortical connections between intact and deafferented cortices. After spinal cord injury supragranular layers exhibit better integration of spontaneous corticocortical information while infragranular layers exhibit better integration of evoked sensory stimulation. Cortical reorganization is a layer-specific phenomenon.

Stimulation of sensory pathways is important for the normal development of cortical sensory areas, and impairments in the normal development can have long-lasting effect on animal's behavior. In particular, disturbances that occur early in development can cause permanent changes in brain structure and function. The behavioral effect of early sensory deprivation was studied in the mouse whisker system using a protocol to induce a 1-week sensory deprivation immediately after birth. Only two rows of whiskers were spared (C and D rows), and the rest were deprived, to create a situation where an unbalanced sensory input, rather than a complete loss of input, causes a reorganization of the sensory map. Sensory deprivation increased the barrel size ratio of the spared CD rows compared with the deprived AB rows; thus, the map reorganization is likely due, at least in part, to a rewiring of thalamocortical projections. The behavioral effect of such a map reorganization was investigated in the gap-crossing task, where the animals used a whisker that was spared during the sensory deprivation. Animals that had been sensory deprived performed equally well with the control animals in the gap-crossing task, but were more active in exploring the gap area and consequently made more approaches to the gap - approaches that on average were of shorter duration. A restricted sensory deprivation of only some whiskers, although it does not seem to affect the overall performance of the animals, does have an effect on their behavioral strategy on executing the gap-crossing task.

A myriad of mechanisms have been suggested to account for the full richness of visual cortical plasticity. We found that visual cortex lacking Arc is impervious to the effects of deprivation or experience. Using intrinsic signal imaging and chronic visually evoked potential recordings, we found that Arc(-/-) mice did not exhibit depression of deprived-eye responses or a shift in ocular dominance after brief monocular deprivation. Extended deprivation also failed to elicit a shift in ocular dominance or open-eye potentiation. Moreover, Arc(-/-) mice lacked stimulus-selective response potentiation. Although Arc(-/-) mice exhibited normal visual acuity, baseline ocular dominance was abnormal and resembled that observed after dark-rearing. These data suggest that Arc is required for the experience-dependent processes that normally establish and modify synaptic connections in visual cortex.