S1 Neurons Research Articles

Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience.

Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon "en passant" boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and Fmr1 KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon "en passant" boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.SIGNIFICANCE STATEMENT Very few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.

Specific translocation of protein kinase Cγ to lipid rafts in primary somatosensory cortex is involved in remifentanil-induced hyperalgesia

Objective To determine the involvement of neuron-specific protein kinase C γ isoform(PKCγ) translocation to lipid rafts in primary somatosensory cortex(S1) in remifentanil-induced hyperalgesia. Methods Fifty adult male SD rats weighing 240-260 g (at the age of 8-10 weeks) were randomly assigned to 3 groups: control, the propofol (group P) and the remifentanil group (group R). Intravenous anesthesia with either propofol (group P) or propofol combined with remifentanil(group R) was performed through a 24 G catheter inserted in tail vein for 3 h. The total doses of propofol were 36.0 mg and 26.0 mg in group P and R, respectively. The dose of remifentanil was 19.5 g in group R. Mechanical allodynia in the rats was evaluated by the von Frey filament test, and PKCγ levels in the whole-cell lysates and lipid rafts in the S1 neurons were determined by Western blot. Results ① The threshold of paw-withdrawal response to von Frey filament stimulation in group R at 2 h after stopping drug infusion was significantly lower than that in group P(P<0.05). ② Two hours after stopping drug infusion, the PKCγ protein levels in the lipid rafts of S1 in group R were significantly higher than those in group R(P<0.05). Conclusions These results suggest that increased translocation of PKCγ to lipid raft of S1 neurons may contribute to postoperative pain in rats after propofol-remifentanil-based anesthesia. Key words: Remifentanil; Hyperalgesia; Protein kinase C γisoform; Lipid rafts; Primary somatosensory cortex

Context-dependent tactile texture-sensitivity in monkey M1 and S1 cortex.

Caudal primary motor cortex (M1, area 4) is sensitive to cutaneous inputs, but the extent to which the physical details of complex stimuli are encoded is not known. We investigated the sensitivity of M1 neurons (4 Macaca mulatta monkeys) to textured stimuli (smooth/rough or rough/rougher) during the performance of a texture discrimination task and, for some cells, during a no-task condition (same surfaces; no response). The recordings were made from the hemisphere contralateral to the stimulated digits; the motor response (sensory decision) was made with the nonstimulated arm. Most M1 cells were modulated during surface scanning in the task (88%), but few of these were texture-related (24%). In contrast, 44% of M1 neurons were texture related in the no-task condition. Recordings from the neighboring primary somatosensory cortex (S1), the potential source of texture-related signals to M1, showed that S1 neurons were significantly more likely to be texture related during the task (57 vs 24%) than M1. No difference was observed in the no-task condition (52 vs. 44%). In these recordings, the details about surface texture were relevant for S1 but not for M1. We suggest that tactile inputs to M1 were selectively suppressed when the animals were engaged in the task. S1 was spared these controls, as the same inputs were task-relevant. Taken together, we suggest that the suppressive effects are most likely exerted directly at the level of M1, possibly through the activation of a top-down gating mechanism specific to motor set/intention. NEW & NOTEWORTHY Sensory feedback is important for motor control, but we have little knowledge of the contribution of sensory inputs to M1 discharge during behavior. We showed that M1 neurons signal changes in tactile texture, but mainly outside the context of a texture discrimination task. Tactile inputs to M1 were selectively suppressed during the task because this input was not relevant for the recorded hemisphere, which played no role in generating the discrimination response.

The increased release of amino acid neurotransmitters of the primary somatosensory cortical area in rats contributes to remifentanil-induced hyperalgesia and its inhibition by lidocaine.

BackgroundStudies have confirmed that activation of the neurons of primary somatosensory cortex (S1) is involved in the process of remifentanil (Remi)-induced hyperalgesia (RIH), which can be suppressed by lidocaine (Lido). A total intravenous anesthesia model of rats mimicking clinical Remi-based anesthesia was set up to explore the release of amino acid neurotransmitters of S1 cortex in RIH and its inhibition by Lido in this study.Materials and methodsSprague Dawley rats were randomly divided into the following four groups: propofol (Pro), Remi, Remi combined Lido, and Lido groups. Mechanical hyperalgesia was evaluated by von Frey test; the amino acid neurotransmitters in the microdialysates of S1 area were detected by high-performance liquid chromatography (HPLC)-fluorescence, and conventional protein kinase C (cPKC)γ levels in the whole-cell lysates and membrane lipid rafts (MLRs) were determined by Western blotting.ResultsThe von Frey test showed that co-administration of Lido significantly inhibited a Remi-induced decrease in the threshold of the paw withdrawal response in Remi group at 2 h postinfusion. Meanwhile, the Remi-induced increases in both the excitatory and inhibitory amino acid releases in S1 were suppressed by co-administrating Lido within 5 h postinfusion. Western blotting showed that the increased cPKCγ level in the membrane lipid rafts (MLR) induced by Remi was also inhibited by Lido.ConclusionThe increased release of amino acid neurotransmitters and the translocation of cPKCγ in MLR suggest the activation of S1 neurons, which may be one of the mechanisms underlying RIH. Lido reduces the release of amino acid neurotransmitters in S1 neurons and the translocation of cPKCγ in MLRs after stopping Remi, which may be one of its antihyperalgesic mechanisms.

Place Cell-Like Activity in the Primary Sensorimotor and Premotor Cortex During Monkey Whole-Body Navigation

Primary motor (M1), primary somatosensory (S1) and dorsal premotor (PMd) cortical areas of rhesus monkeys previously have been associated only with sensorimotor control of limb movements. Here we show that a significant number of neurons in these areas also represent body position and orientation in space. Two rhesus monkeys (K and M) used a wheelchair controlled by a brain-machine interface (BMI) to navigate in a room. During this whole-body navigation, the discharge rates of M1, S1, and PMd neurons correlated with the two-dimensional (2D) room position and the direction of the wheelchair and the monkey head. This place cell-like activity was observed in both monkeys, with 44.6% and 33.3% of neurons encoding room position in monkeys K and M, respectively, and the overlapping populations of 41.0% and 16.0% neurons encoding head direction. These observations suggest that primary sensorimotor and premotor cortical areas in primates are likely involved in allocentrically representing body position in space during whole-body navigation, which is an unexpected finding given the classical hierarchical model of cortical processing that attributes functional specialization for spatial processing to the hippocampal formation.

Neural Coding of Whisker-Mediated Touch in Primary Somatosensory Cortex Is Altered Following Early Blindness.

Sensory systems do not develop and function independently of one another, yet they are typically studied in isolation. Effects of multisensory interactions on the developing neocortex can be revealed by altering the ratios of incoming sensory inputs associated with different modalities. We investigated neural responses in primary somatosensory cortex (S1) of short-tailed opossums (Monodelphis domestica; either sex) after the elimination of visual input through bilateral enucleation very early in development. To assess the influence of tactile experience after vision loss, we also examined naturally occurring patterns of exploratory behavior. In early blind (EB) animals, overall levels of tactile experience were similar to those of sighted controls (SC); locomotor activity was unimpaired and accompanied by whisking. Using extracellular single-unit recording techniques under anesthesia, we found that EB animals exhibited a reduction in the magnitude of neural responses to whisker stimuli in S1, coupled with spatial sharpening of receptive fields, in comparison to SC animals. These alterations manifested as two different effects on sensory processing in S1 of EB animals: the ability of neurons to detect single whisker stimulation was decreased, whereas their ability to discriminate between stimulation of neighboring whiskers was enhanced. The increased selectivity of S1 neurons in EB animals was reflected in improved population decoding performance for whisker stimulus position, particularly along the rostrocaudal axis of the snout, which aligns with the primary axis of natural whisker motion. These findings suggest that a functionally distinct form of somatosensory plasticity occurs when vision is lost early in development.SIGNIFICANCE STATEMENT After sensory loss, compensatory behavior mediated through the spared senses could be generated entirely through the recruitment of brain areas associated with the deprived sense. Alternatively, functional compensation in spared modalities may be achieved through a combination of plasticity in brain areas corresponding to both spared and deprived sensory modalities. Although activation of neurons in cortex associated with a deprived sense has been described frequently, it is unclear whether this is the only substrate available for compensation or if plasticity within cortical fields corresponding to spared modalities, particularly primary sensory cortices, may also contribute. Here, we demonstrate empirically that early loss of vision alters coding of sensory inputs in primary somatosensory cortex in a manner that supports enhanced tactile discrimination.

Postnatal Ablation of Synaptic Retinoic Acid Signaling Impairs Cortical Information Processing and Sensory Discrimination in Mice.

Retinoic acid (RA) and its receptors (RARs) are well established essential transcriptional regulators during embryonic development. Recent findings in cultured neurons identified an independent and critical post-transcriptional role of RA and RARα in the homeostatic regulation of excitatory and inhibitory synaptic transmission in mature neurons. However, the functional relevance of synaptic RA signaling in vivo has not been established. Here, using somatosensory cortex as a model system and the RARα conditional knock-out mouse as a tool, we applied multiple genetic manipulations to delete RARα postnatally in specific populations of cortical neurons, and asked whether synaptic RA signaling observed in cultured neurons is involved in cortical information processing in vivo Indeed, conditional ablation of RARα in mice via a CaMKIIα-Cre or a layer 5-Cre driver line or via somatosensory cortex-specific viral expression of Cre-recombinase impaired whisker-dependent texture discrimination, suggesting a critical requirement of RARα expression in L5 pyramidal neurons of somatosensory cortex for normal tactile sensory processing. Transcranial two-photon imaging revealed a significant increase in dendritic spine elimination on apical dendrites of somatosensory cortical layer 5 pyramidal neurons in these mice. Interestingly, the enhancement of spine elimination is whisker experience-dependent as whisker trimming rescued the spine elimination phenotype. Additionally, experiencing an enriched environment improved texture discrimination in RARα-deficient mice and reduced excessive spine pruning. Thus, RA signaling is essential for normal experience-dependent cortical circuit remodeling and sensory processing.SIGNIFICANCE STATEMENT The importance of synaptic RA signaling has been demonstrated in in vitro studies. However, whether RA signaling mediated by RARα contributes to neural circuit functions in vivo remains largely unknown. In this study, using a RARα conditional knock-out mouse, we performed multiple regional/cell-type-specific manipulation of RARα expression in the postnatal brain, and show that RARα signaling contributes to normal whisker-dependent texture discrimination as well as regulating spine dynamics of apical dendrites from layer (L5) pyramidal neurons in S1. Deletion of RARα in excitatory neurons in the forebrain induces elevated spine elimination and impaired sensory discrimination. Our study provides novel insights into the role of RARα signaling in cortical processing and experience-dependent spine maturation.

A Non-canonical Feedback Circuit for Rapid Interactions between Somatosensory Cortices

SUMMARYSensory perception depends on interactions among cortical areas. These interactions are mediated by canonical patterns of connectivity in which higher areas send feedback projections to lower areas via neurons in superficial and deep layers. Here, we probed the circuit basis of interactions among two areas critical for touch perception in mice, whisker primary (wS1) and secondary (wS2) somatosensory cortices. Neurons in layer 4 of wS2 (S2L4) formed a major feedback pathway to wS1. Feedback from wS2 to wS1 was organized somatotopically. Spikes evoked by whisker deflections occurred nearly as rapidly in wS2 as in wS1, including among putative S2L4 → S1 feedback neurons. Axons from S2L4 → S1 neurons sent stimulus orientation-specific activity to wS1. Optogenetic excitation of S2L4 neurons modulated activity across both wS2 and wS1, while inhibition of S2L4 reduced orientation tuning among wS1 neurons. Thus, a non-canonical feedback circuit, originating in layer 4 of S2, rapidly modulates early tactile processing.

Loss of inhibition in ipsilateral somatosensory areas following altered afferent nerve signaling from the hand

Cutaneous stimulation of the hand results in increased neural activity in the contralateral primary somatosensory cortex (S1) in humans, whereas an inhibition of neurons is seen in the ipsilateral S1.The aim of this study was to assess changes in neural activity in the S1 bilaterally, with a focus on the ipsilateral hemisphere, following altered afferent nerve signaling from the hand. Three cohorts, all with altered afferent nerve signaling from the hand, participated in the study. There were: 18 patients with traumatic median nerve injury, 10 patients with vibration induced neuropathy and 11 healthy subjects who had their dominant hand and wrist immobilized for 72 h. In addition, 36 healthy subjects were included as controls. Each subject was examined using functional magnetic resonance imaging at 3 T. All three study cohorts showed enlarged activation in the contralateral S1 during tactile stimulation compared to healthy controls. Moreover, inhibition of the ipsilateral S1 was significantly decreased or completely lost. Thus, somatosensory areas of both hemispheres respond to changed afferent nerve signaling from the hand. The loss of inhibition of neurons in the ipsilateral S1 suggests an important role of the ipsilateral hemisphere in the cerebral adaptation following a change in afferent nerve signaling.

Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: the impact of serotypes and promoters.

Recombinant adeno-associated virus (rAAV) vector-mediated gene transfer into genetically defined neuron subtypes has become a powerful tool to study the neuroanatomy of neuronal circuits in the brain and to unravel their functions. More recently, this methodology has also become popular for the analysis of spinal cord circuits. To date, a variety of naturally occurring AAV serotypes and genetically modified capsid variants are available but transduction efficiency in spinal neurons, target selectivity, and the ability for retrograde tracing are only incompletely characterized. Here, we have compared the transduction efficiency of seven commonly used AAV serotypes after intraspinal injection. We specifically analyzed local transduction of different types of dorsal horn neurons, and retrograde transduction of dorsal root ganglia (DRG) neurons and of neurons in the rostral ventromedial medulla (RVM) and the somatosensory cortex (S1). Our results show that most of the tested rAAV vectors have similar transduction efficiency in spinal neurons. All serotypes analyzed were also able to transduce DRG neurons and descending RVM and S1 neurons via their spinal axon terminals. When comparing the commonly used rAAV serotypes to the recently developed serotype 2 capsid variant rAAV2retro, a >20-fold increase in transduction efficiency of descending supraspinal neurons was observed. Conversely, transgene expression in retrogradely transduced neurons was strongly reduced when the human synapsin 1 (hSyn1) promoter was used instead of the strong ubiquitous hybrid cytomegalovirus enhancer/chicken β-actin promoter (CAG) or cytomegalovirus (CMV) promoter fragments. We conclude that the use of AAV2retro greatly increases transduction of neurons connected to the spinal cord via their axon terminals, while the hSyn1 promoter can be used to minimize transgene expression in retrogradely connected neurons of the DRG or brainstem. Cover Image for this issue: doi. 10.1111/jnc.13813.

Cortical neurons multiplex reward-related signals along with sensory and motor information

Rewards are known to influence neural activity associated with both motor preparation and execution. This influence can be exerted directly upon the primary motor (M1) and somatosensory (S1) cortical areas via the projections from reward-sensitive dopaminergic neurons of the midbrain ventral tegmental areas. However, the neurophysiological manifestation of reward-related signals in M1 and S1 are not well understood. Particularly, it is unclear how the neurons in these cortical areas multiplex their traditional functions related to the control of spatial and temporal characteristics of movements with the representation of rewards. To clarify this issue, we trained rhesus monkeys to perform a center-out task in which arm movement direction, reward timing, and magnitude were manipulated independently. Activity of several hundred cortical neurons was simultaneously recorded using chronically implanted microelectrode arrays. Many neurons (9-27%) in both M1 and S1 exhibited activity related to reward anticipation. Additionally, neurons in these areas responded to a mismatch between the reward amount given to the monkeys and the amount they expected: A lower-than-expected reward caused a transient increase in firing rate in 60-80% of the total neuronal sample, whereas a larger-than-expected reward resulted in a decreased firing rate in 20-35% of the neurons. Moreover, responses of M1 and S1 neurons to reward omission depended on the direction of movements that led to those rewards. These observations suggest that sensorimotor cortical neurons corepresent rewards and movement-related activity, presumably to enable reward-based learning.

Rate and Temporal Coding Convey Multisensory Information in Primary Sensory Cortices.

Optimal behavior and survival result from integration of information across sensory systems. Modulation of network activity at the level of primary sensory cortices has been identified as a mechanism of cross-modal integration, yet its cellular substrate is still poorly understood. Here, we uncover the mechanisms by which individual neurons in primary somatosensory (S1) and visual (V1) cortices encode visual-tactile stimuli. For this, simultaneous extracellular recordings were performed from all layers of the S1 barrel field and V1 in Brown Norway rats in vivo and units were clustered and assigned to pyramidal neurons (PYRs) and interneurons (INs). We show that visual-tactile stimulation modulates the firing rate of a relatively low fraction of neurons throughout all cortical layers. Generally, it augments the firing of INs and decreases the activity of PYRs. Moreover, bimodal stimulation shapes the timing of neuronal firing by strengthening the phase-coupling between neuronal discharge and theta–beta band network oscillations as well as by modulating spiking onset. Sparse direct axonal projections between neurons in S1 and V1 seem to time the spike trains between the two cortical areas and, thus, may act as a substrate of cross-modal modulation. These results indicate that few cortical neurons mediate multisensory effects in primary sensory areas by directly encoding cross-modal information by their rate and timing of firing.

An Ultrastructural Study of the Thalamic Input to Layer 4 of Primary Motor and Primary Somatosensory Cortex in the Mouse.

The traditional classification of primary motor cortex (M1) as an agranular area has been challenged recently when a functional layer 4 (L4) was reported in M1. L4 is the principal target for thalamic input in sensory areas, which raises the question of how thalamocortical synapses formed in M1 in the mouse compare with those in neighboring sensory cortex (S1). We identified thalamic boutons by their immunoreactivity for the vesicular glutamate transporter 2 (VGluT2) and performed unbiased disector counts from electron micrographs. We discovered that the thalamus contributed proportionately only half as many synapses to the local circuitry of L4 in M1 compared with S1. Furthermore, thalamic boutons in M1 targeted spiny dendrites exclusively, whereas ∼9% of synapses were formed with dendrites of smooth neurons in S1. VGluT2+ boutons in M1 were smaller and formed fewer synapses per bouton on average (1.3 vs 2.1) than those in S1, but VGluT2+ synapses in M1 were larger than in S1 (median postsynaptic density areas of 0.064 μm2 vs 0.042 μm2). In M1 and S1, thalamic synapses formed only a small fraction (12.1% and 17.2%, respectively) of all of the asymmetric synapses in L4. The functional role of the thalamic input to L4 in M1 has largely been neglected, but our data suggest that, as in S1, the thalamic input is amplified by the recurrent excitatory connections of the L4 circuits. The lack of direct thalamic input to inhibitory neurons in M1 may indicate temporal differences in the inhibitory gating in L4 of M1 versus S1.SIGNIFICANCE STATEMENT Classical interpretations of the function of primary motor cortex (M1) emphasize its lack of the granular layer 4 (L4) typical of sensory cortices. However, we show here that, like sensory cortex (S1), mouse M1 also has the canonical circuit motif of a core thalamic input to the middle cortical layer and that thalamocortical synapses form a small fraction (M1: 12%; S1: 17%) of all asymmetric synapses in L4 of both areas. Amplification of thalamic input by recurrent local circuits is thus likely to be a significant mechanism in both areas. Unlike M1, where thalamocortical boutons typically form a single synapse, thalamocortical boutons in S1 usually formed multiple synapses, which means they can be identified with high probability in the electron microscope without specific labeling.

Shaping the Output of Lumbar Flexor Motoneurons by Sacral Neuronal Networks.

Spinal central pattern generators (CPGs) produce the rhythmic output required for coordinating stepping and stabilizing the body axis during movements. Electrical stimulation and exogenous drugs can reactivate the spinal CPGs and improve the motor function in the absence of descending supraspinal control. Since the body-stabilizing sacral networks can activate and modulate the limb-moving lumbar circuitry, it is important to clarify the functional organization of sacral and lumbar networks and their linking pathways. Here we decipher the ascending circuitry linking adrenoceptor-activated sacral CPGs and lumbar flexor motoneurons, thereby providing novel insights into mechanisms by which sacral circuitry recruits lumbar flexors, and enhances the motor output during lumbar afferent-induced locomotor rhythms. Moreover, our findings might help to improve drug/electrical stimulation-based therapy to accelerate locomotor-based rehabilitation.

Comparison of spontaneous activity of somatosensory cortical neurons under pentobarbital and urethane anesthesia by using in vivo patch-clamp

Objective Using in vivo perforated whole-cell recording in adult rats, we compared the spontaneous activity of somatosensory cortical(S1) neurons that was recorded under light pentobarbital and urethane anesthesia. Methods Twenty SD male rats were anesthetized with either pentobarbital or urethane(10 rats in each group), and head of the rat was fixed with stereotaxic apparatus for surgery and the following procedures. Perforated whole-cell recording was performed in vivo in the anesthetized animals several hours after surgery. Results Twenty-seven S1 neurons recorded from each group of rats were randomly selected for analysis. There were no significant differences in the resting membrane potential[(-84±4) mV vs (-82±4) mV, P>0.05], action-potential frequency [(0.28±0.28) Hz vs (0.33±0.34) Hz, P>0.05], and action-potential amplitude[(58±10) mV vs (63±8) mV, P>0.05] between these two groups. However, the patterns of membrane-potential change were significantly different between the two groups. Under pentobarbital anesthesia, Membrane-potential changes exhibited a short duration, and their cumulative distribution fell in a unimodal curve. Under urethane anesthesia, membrane-potential changes exhibited a long duration and consisted of both persistent UP and DOWN states, and their cumulative distribution fell in a bimodal curve. Conclusions Pentobarbital and urethane anesthesia lead to distinct patterns of membrane-potential changes in somatosensory cortical neurons. Key words: Pentobarbital; Urethane; Somatosensory cortex; Membrane-potential

Dynamics of Propofol-Induced Loss of Consciousness Across Primate Neocortex.

The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.

Sensory and decision-related activity propagate in a cortical feedback loop during touch perception.

The brain transforms physical sensory stimuli into meaningful perceptions. In animals making choices about sensory stimuli, neuronal activity in successive cortical stages reflects a progression from sensation to decision. Feedforward and feedback pathways connecting cortical areas are critical for this transformation. However, the computational roles of these pathways are poorly understood because pathway-specific activity has rarely been monitored during a perceptual task. Using cellular-resolution, pathway-specific imaging, we measured neuronal activity across primary (S1) and secondary (S2) somatosensory cortices of mice performing a tactile detection task. S1 encoded the stimulus better than S2, while S2 activity more strongly reflected perceptual choice. S1 neurons projecting to S2 fed forward activity that predicted choice. Activity encoding touch and choice propagated in an S1–S2 loop along feedforward and feedback axons. Our results suggest that sensory inputs converge into a perceptual outcome as feedforward computations are reinforced in a feedback loop.

Target-specific M1 inputs to infragranular S1 pyramidal neurons.

The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237-2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.

Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis.

BackgroundChronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35–55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear.We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS.MethodsWe used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs.ResultsMice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity—but did not significantly attenuate the loss of PNNs.ConclusionsThese findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0609-4) contains supplementary material, which is available to authorized users.

Golgi Analysis of Neuron Morphology in the Presumptive Somatosensory Cortex and Visual Cortex of the Florida Manatee (Trichechus manatus latirostris)

The current study investigates neuron morphology in presumptive primary somatosensory (S1) and primary visual (V1) cortices of the Florida manatee (Trichechus manatus latirostris) as revealed by Golgi impregnation. Sirenians, including manatees, have an aquatic lifestyle, a large body size, and a relatively large lissencephalic brain. The present study examines neuron morphology in 3 cortical areas: in S1, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2) and in V1, dorsolateral cortex area 4 (DL4). Neurons exhibited a variety of morphological types, with pyramidal neurons being the most common. The large variety of neuron types present in the manatee cortex was comparable to that seen in other eutherian mammals, except for rodents and primates, where pyramid-shaped neurons predominate. A comparison between pyramidal neurons in S1 and V1 indicated relatively greater dendritic branching in S1. Across all 3 areas, the dendritic arborization pattern of pyramidal neurons was also similar to that observed previously in the afrotherian rock hyrax, cetartiodactyls, opossums, and echidnas but did not resemble the widely bifurcated dendrites seen in the large-brained African elephant. Despite adaptations for an aquatic environment, manatees did not share specific neuron types such as tritufted and star-like neurons that have been found in cetaceans. Manatees exhibit an evolutionarily primitive pattern of cortical neuron morphology shared with most other mammals and do not appear to have neuronal specializations for an aquatic niche.