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1.  Effect of limb lengthening on internodal length and conduction velocity of peripheral nerve 
The influences of axon diameter, myelin thickness and internodal length on the velocity of conduction of peripheral nerve action potentials are unclear. Previous studies have demonstrated a strong dependence of conduction velocity on internodal length. However, a theoretical analysis has suggested that this relationship may be lost above a nodal separation of about 0.6 mm. Here we measured nerve conduction velocities in a rabbit model of limb lengthening that produced compensatory increases in peripheral nerve growth. Divided tibial bones in one hind limb were gradually lengthened at 0.7 mm per day using an external frame attached to the bone. This was associated with a significant increase (33%) of internodal length (0.95 to 1.3 mm) in axons of the tibial nerve that varied in proportion to the mechanical strain in the nerve of the lengthened limb. Axonal diameter, myelin thickness and g-ratios were not significantly altered by limb-lengthening. Despite the substantial increase in internodal length, no significant change was detected in conduction velocity (about 43 ms-1) measured either in vivo or in isolated tibial nerves. The results demonstrate that the internode remains plastic in the adult but that increases in internodal length of myelinated adult nerve axons do not result in either deficiency or proportionate increases in their conduction velocity and supports the view that the internodal lengths of nerves reach a plateau beyond which their conduction velocities are no longer sensitive to increases in internodal length.
doi:10.1523/JNEUROSCI.4176-12.2013
PMCID: PMC4335134  PMID: 23467369
2.  Encoding of Sensory Prediction Errors in the Human Cerebellum 
A central tenet of motor neuroscience is that the cerebellum learns from sensory prediction errors. Surprisingly, neuroimaging studies have not revealed definitive signatures of error processing in the cerebellum. Furthermore, neurophysiologic studies suggest an asymmetry, such that the cerebellum may encode errors arising from unexpected sensory events, but not errors reflecting the omission of expected stimuli. We conducted an imaging study to compare the cerebellar response to these two types of errors. Participants made fast out-and-back reaching movements, aiming either for an object that delivered a force pulse if intersected or for a gap between two objects, either of which delivered a force pulse if intersected. Errors (missing the target) could therefore be signaled either through the presence or absence of a force pulse. In an initial analysis, the cerebellar BOLD response was smaller on trials with errors compared with trials without errors. However, we also observed an error-related decrease in heart rate. After correcting for variation in heart rate, increased activation during error trials was observed in the hand area of lobules V and VI. This effect was similar for the two error types. The results provide evidence for the encoding of errors resulting from either the unexpected presence or unexpected absence of sensory stimulation in the human cerebellum.
doi:10.1523/JNEUROSCI.4504-11.2012
PMCID: PMC4332713  PMID: 22492047
3.  Distinct roles of GABAA and GABAB receptors in balancing and terminating persistent cortical activity 
Cortical networks spontaneously fluctuate between persistently active UP states and quiescent DOWN states. The UP states are maintained by recurrent excitation within local circuits, and can be turned on and off by synaptic input. GABAergic inhibition is believed to be important for stabilizing such persistent activity by balancing the excitation, and could have an additional role in terminating the UP state. Here we report that GABAA and GABAB receptor-mediated inhibition have distinct and complementary roles in balancing and terminating persistent activity. In a model of UP-DOWN states expressed in slices of rat entorhinal cortex, the GABAA receptor antagonist, gabazine (50-500 nM), concentration-dependently decreased UP state duration, eventually leading to epileptiform bursts. In contrast, the GABAB receptor antagonist, CGP55845 (50 nM – 1 μM), increased the duration of persistent network activity, and prevented stimulus-induced DOWN state transitions. These results suggest that while GABAA receptor-mediated inhibition is necessary for balancing persistent activity, activation of GABAB receptors contributes to terminating UP states.
doi:10.1523/JNEUROSCI.6162-08.2009
PMCID: PMC4326656  PMID: 19515919
GABA; inhibition; network; persistent activity; UP/DOWN states; entorhinal cortex
4.  Developmental Changes in Short-Term Plasticity at the Rat Calyx of Held Synapse 
The calyx of Held synapse of the medial nucleus of the trapezoid body functions as a relay synapse in the auditory brainstem. In vivo recordings have shown that this synapse displays low release probability and that the average size of synaptic potentials does not depend on recent history. We used a ventral approach to make in vivo extracellular recordings from the calyx of Held synapse in rats aged postnatal day 4 (P4) to P29 to study the developmental changes that allow this synapse to function as a relay. Between P4 and P8, we observed evidence for the presence of large short-term depression, which was counteracted by short-term facilitation at short intervals. Major changes occurred in the last few days before the onset of hearing for air-borne sounds, which happened at P13. The bursting pattern changed into a primary-like pattern, the amount of depression and facilitation decreased strongly, and the decay of facilitation became much faster. Whereas short-term plasticity was the most important cause of variability in the size of the synaptic potentials in immature animals, its role became minor around hearing onset and afterward. Similar developmental changes were observed during stimulation experiments both in brain slices and in vivo following cochlear ablation. Our data suggest that the strong reduction in release probability and the speedup of the decay of synaptic facilitation that happen just before hearing onset are important events in the transformation of the calyx of Held synapse into an auditory relay synapse.
doi:10.1523/JNEUROSCI.1995-11.2011
PMCID: PMC4314708  PMID: 21832200
5.  Toll-Like Receptor 3 Is a Potent Negative Regulator of Axonal Growth in Mammals 
Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine:polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor κB. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.
doi:10.1523/JNEUROSCI.4290-06.2007
PMCID: PMC4313565  PMID: 18032677
Toll-like receptor-3; axon; polyinosine:polycytidylic acid; poly I:C; RNA; CNS; danger theory
6.  Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter 
Periventricular leukomalacia is the predominant injury in the preterm infant leading to cerebral palsy. Oxygen exposure may be an additional cause of brain injury in these infants. In this study, we investigated pathways of maturation-dependent oligodendrocyte (OL) death induced by hyperoxia in vitro and in vivo. Developing and mature OLs were subjected to 80% oxygen (0–24 h). Lactate dehydrogenase (LDH) assay was used to assess cell viability. Furthermore, 3-, 6-, and 10-d-old rat pups were subjected to 80% oxygen (24 h), and their brains were processed for myelin basic protein staining. Significant cell death was detected after 6–24 h incubation in 80% oxygen in pre-OLs (O4+,O1−), but not in mature OLs (MBP+). Cell death was executed by a caspase-dependent apoptotic pathway and could be blocked by the pan-caspase inhibitor zVAD-fmk. Overexpression of BCL2 (Homo sapiens B-cell chronic lymphocytic leukemia/lymphoma 2) significantly reduced apoptosis. Accumulation of superoxide and generation of reactive oxygen species (ROS) were detected after 2 h of oxygen exposure. Lipoxygenase inhibitors 2,3,5-trimethyl-6-(12-hydroxy-5–10-dodecadiynyl-1,4-benzoquinone and N-benzyl-N-hydroxy-5-phenylpentamide fully protected the cells from oxidative injury. Overexpression of superoxide dismutase (SOD1) dramatically increased injury to pre-OLs but not to mature OLs. We extended these studies by testing the effects of hyperoxia on neonatal white matter. Postnatal day 3 (P3) and P6 rats, but not P10 pups, showed bilateral reduction in MBP (myelin basic protein) expression with 24 h exposure to 80% oxygen. Hyperoxia causes oxidative stress and triggers maturation-dependent apoptosis in pre-OLs, which involves the generation of ROS and caspase activation, and leads to white matter injury in the neonatal rat brain. These observations may be relevant to white matter injury observed in premature infants.
doi:10.1523/JNEUROSCI.3213-07.2008
PMCID: PMC4305399  PMID: 18234901
oxidative stress; periventricular leukomalacia; development; oligodendrocyte; apoptosis; lipoxygenase inhibitors
7.  Fibroblast Growth Factor-Regulated Palmitoylation of the Neural Cell Adhesion Molecule Determines Neuronal Morphogenesis 
During development of the nervous system, short- and long-range signals cooperate to promote axonal growth, guidance, and target innervation. Particularly, a short-range signal transducer, the neural cell adhesion molecule (NCAM), stimulates neurite outgrowth via mechanisms that require posttranslational modification of NCAM and signaling via receptors to a long-range messenger, the fibroblast growth factor (FGF). In the present study we further characterized a mechanism which regulates the functional interplay between NCAM and FGF receptor(s). We show that activation of FGF receptor(s) by FGF2 leads to palmitoylation of the two major transmembrane NCAM isoforms, NCAM140 and NCAM180, translocation of NCAM to GM1 ganglioside-containing lipid rafts, and stimulation of neurite outgrowth of hippocampal neurons. Ablation of NCAM, mutation of NCAM140 or NCAM180 palmitoylation sites, or pharmacological suppression of NCAM signaling inhibited FGF2-stimulated neurite outgrowth. Of the 23 members of the aspartate-histidine-histidine-cysteine (DHHC) domain containing proteins, DHHC-7 most strongly stimulated palmitoylation of NCAM, and enzyme activity was enhanced by FGF2. Thus, our study uncovers a molecular mechanism by which a growth factor regulates neuronal morphogenesis via activation of palmitoylation, which in turn modifies subcellular location and thus signaling via an adhesion molecule.
doi:10.1523/JNEUROSCI.2171-08.2008
PMCID: PMC4301590  PMID: 18768683
acylation; palmitoylation; cell adhesion; growth factor; lipid raft; neurite outgrowth; FLIM; FRET; hippocampus
8.  Arrest of Myelination and Reduced Axon Growth when Schwann Cells Lack mTOR 
In developing peripheral nerves differentiating Schwann cells sort individual axons from bundles and ensheath them to generate multiple layers of myelin. In recent years there has been an increasing understanding of the extracellular and intracellular factors that initiate and stimulate Schwann cell myelination together with a growing appreciation of some of the signalling pathways involved. However, our knowledge of how Schwann cell growth is regulated during myelination is still incomplete. The mammalian target of rapamycin (mTOR) is a core kinase in two major complexes, mTORC1 and mTORC2, that regulate cell growth and differentiation in a variety of mammalian cells. Here we show that elimination of mTOR from murine Schwann cells prevented neither radial sorting nor the initiation of myelination. However, normal post-natal growth of myelinating Schwann cells, both radially and longitudinally, was highly retarded. The myelin sheath in the mutant was much thinner than normal; nevertheless, sheath thickness relative to axon diameter (g-ratio) remained constant in both wild-type and mutant nerves from P14 to P90. Although axon diameters were normal in the mutant at the initiation of myelination, further growth as myelination proceeded was retarded, and this was associated with reduced phosphorylation of neurofilaments. Consistent with thinner axonal diameters and internodal lengths, conduction velocities in mutant quadriceps nerves were also reduced. These data establish a critical role for mTOR signalling in both the longitudinal and radial growth of the myelinating Schwann cell.
doi:10.1523/JNEUROSCI.4814-11.2012
PMCID: PMC4298696  PMID: 22302821
9.  In Vivo Microdialysis Reveals Age-Dependent Decrease of Brain Interstitial Fluid Tau Levels in P301S Human Tau Transgenic Mice 
Although tau is a cytoplasmic protein, it is also found in brain extracellular fluids, e.g., CSF. Recent findings suggest that aggregated tau can be transferred between cells and extracellular tau aggregates might mediate spread of tau pathology. Despite these data, details of whether tau is normally released into the brain interstitial fluid (ISF), its concentration in ISF in relation to CSF, and whether ISF tau is influenced by its aggregation are unknown. To address these issues, we developed a microdialysis technique to analyze monomeric ISF tau levels within the hippocampus of awake, freely moving mice. We detected tau in ISF of wild-type mice, suggesting that tau is released in the absence of neurodegeneration. ISF tau was significantly higher than CSF tau and their concentrations were not significantly correlated. Using P301S human tau transgenic mice (P301S tg mice), we found that ISF tau is fivefold higher than endogenous murine tau, consistent with its elevated levels of expression. However, following the onset of tau aggregation, monomeric ISF tau decreased markedly. Biochemical analysis demonstrated that soluble tau in brain homogenates decreased along with the deposition of insoluble tau. Tau fibrils injected into the hippocampus decreased ISF tau, suggesting that extracellular tau is in equilibrium with extracellular or intracellular tau aggregates. This technique should facilitate further studies of tau secretion, spread of tau pathology, the effects of different disease states on ISF tau, and the efficacy of experimental treatments.
doi:10.1523/JNEUROSCI.2569-11.2011
PMCID: PMC4299126  PMID: 21917794
10.  Preynaptic induction and expression of t-LTD demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist 
N-methyl-d-aspartate (NMDA) receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). In order to help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist, MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. To demonstrate the potential of this new method, we investigated timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use-dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses.
doi:10.1523/JNEUROSCI.0274-11.2011
PMCID: PMC4299820  PMID: 21653860
Mouse; barrel cortex; LTD; NMDA; MK801; photolysis
11.  [No title available] 
PMCID: PMC4293915  PMID: 23804108
12.  Subunit- and pathway-specific localization of NMDA receptors and scaffolding proteins at ganglion cell synapses in rat retina 
Retinal ganglion cells (RGCs) receive excitatory glutamatergic input from ON and OFF bipolar cells in distinct sublaminae of the inner plexiform layer (IPL). AMPA and NMDA receptors (AMPARs and NMDARs) mediate excitatory inputs in both synaptic layers, but specific roles for NMDARs at RGC synapses remain unclear. NMDARs comprise NR1 and NR2 subunits and are anchored by membrane associated guanylate kinases (MAGUKs), but it is unknown whether particular NR2 subunits associate preferentially with particular NR1 splice variants and MAGUKs. Here, we used postembedding immunogold electron microscopy (EM) techniques to examine the subsynaptic localization of NMDAR subunits and MAGUKs at ON and OFF synapses onto rat RGCs. We found that the NR2A subunit, the NR1C2‘ splice variant and MAGUKs PSD-95 and PSD-93 are localized to the postsynaptic density (PSD), preferentially at OFF synapses, whereas the NR2B subunit, the NR1C2 splice variant and the MAGUK SAP102 are localized perisynaptically, with NR2B exhibiting a preference for ON synapses. Consistent with these anatomical data, spontaneous EPSCs (sEPSCs) recorded from OFF cells exhibited an NMDAR component that was insensitive to the NR2B antagonist Ro 25-6981. In ON cells, sEPSCs expressed an NMDAR component, partially sensitive to Ro 25-6981, only when glutamate transport was inhibited, indicating perisynaptic expression of NR2B NMDARs. These results provide the first evidence for preferential association of particular NR1 splice variants, NR2 subunits and MAGUKs at central synapses and suggest that different NMDAR subtypes may play specific roles at functionally distinct synapses in the retinal circuitry.
doi:10.1523/JNEUROSCI.5602-08.2009
PMCID: PMC4283557  PMID: 19339621
13.  Motor Commands Induce Time Compression for Tactile Stimuli 
Saccades cause compression of visual space around the saccadic target, and also a compression of time, both phenomena thought to be related to the problem of maintaining saccadic stability (Morrone et al., 2005; Burr and Morrone, 2011). Interestingly, similar phenomena occur at the time of hand movements, when tactile stimuli are systematically mislocalized in the direction of the movement (Dassonville, 1995; Watanabe et al., 2009). In this study, we measured whether hand movements also cause an alteration of the perceived timing of tactile signals. Human participants compared the temporal separation between two pairs of tactile taps while moving their right hand in response to an auditory cue. The first pair of tactile taps was presented at variable times with respect to movement with a fixed onset asynchrony of 150 ms. Two seconds after test presentation, when the hand was stationary, the second pair of taps was delivered with a variable temporal separation. Tactile stimuli could be delivered to either the right moving or left stationary hand. When the tactile stimuli were presented to the motor effector just before and during movement, their perceived temporal separation was reduced. The time compression was effector-specific, as perceived time was veridical for the left stationary hand. The results indicate that time intervals are compressed around the time of hand movements. As for vision, the mislocalizations of time and space for touch stimuli may be consequences of a mechanism attempting to achieve perceptual stability during tactile exploration of objects, suggesting common strategies within different sensorimotor systems.
doi:10.1523/JNEUROSCI.2782-13.2014
PMCID: PMC4112941  PMID: 24990936
action; sensory-motor; time perception; touch
14.  Activity of Neurochemically Heterogeneous Dopaminergic Neurons in the Substantia Nigra during Spontaneous and Driven Changes in Brain State 
Dopaminergic neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are collectively implicated in motor- and reward-related behaviors. However, dopaminergic SN and VTA neurons differ on several functional levels, and dopaminergic SN neurons themselves vary in their intrinsic electrical properties, neurochemical characteristics and connections. This heterogeneity is not only important for normal function; calbindin (CB) expression by some dopaminergic SN neurons has been linked with their increased survival in Parkinson’s disease. To test whether the activity of CB-negative and CB-positive dopaminergic SN neurons differs during distinct spontaneous and driven brain states, we recorded single units in anesthetized rats before, during and after aversive somatosensory stimuli. Recorded neurons were juxtacellularly labeled, confirmed to be dopaminergic, and tested for CB immunoreactivity. During cortical slow-wave activity, the firing of most dopaminergic neurons was slow and regular/irregular and unrelated to cortical slow oscillations. During spontaneous cortical activation, dopaminergic SN neurons fired in a more regular manner, with fewer bursts, but did not change their firing rate. Regardless of brain state, CB-negative dopaminergic neurons fired significantly faster than CB-positive dopaminergic neurons. This difference in firing rate was not mirrored by different firing patterns. Most CB-negative and CB-positive dopaminergic neurons did not respond to the aversive stimuli; of those that did respond, most were inhibited. We conclude that CB-negative and CB-positive dopaminergic neurons exhibit different activities in vivo. Furthermore, the firing of dopaminergic SN neurons is brain state-dependent, and, unlike dopaminergic VTA neurons, they are not commonly recruited or inhibited by aversive stimuli.
doi:10.1523/JNEUROSCI.4423-08.2009
PMCID: PMC4262786  PMID: 19261887
15.  Response Disengagement on a Spatial Self-ordered Sequencing Task: Effects of regionally selective excitotoxic lesions and serotonin depletion within the Prefrontal Cortex 
Prefrontal cortex (PFC) is critical for self-ordered response sequencing. Patients with frontal lobe damage are impaired on response sequencing tasks and increased blood flow has been reported in ventrolateral and dorsolateral PFC in subjects performing such tasks. Previously, we have shown that large excitotoxic lesions of the lateral prefrontal cortex (LPFC) and orbitofrontal cortex (OFC), but not global prefrontal dopamine depletion, markedly impaired marmoset performance on a spatial self-ordered sequencing task (SSOST). To determine whether LPFC or OFC was responsible for the previously observed impairments and whether the underlying neural mechanism was modulated by serotonin, the present study compared the effects of selective LPFC and OFC excitotoxic lesions and 5,7 dihydroxytryptamine induced PFC serotonin depletions in marmosets on SSOST performance.
Severe and long lasting impairments in SSOST performance, including robust perseverative responding, followed LPFC, but not OFC lesions. The deficit was ameliorated by task manipulations that precluded perseveration. Depletions of serotonin within LPFC and OFC had no effect, despite impairing performance on a visual discrimination reversal task, thus providing further evidence for differential monaminergic regulation of prefrontal function. In the light of the proposed attentional control functions of ventrolateral PFC and the failure of LPFC lesioned animals to disengage from the immediately preceding response it is proposed that this deficit may be due to a failure to attend to, and register that a response has been made and thus should not be repeated. However, 5-HT does not appear to be implicated in this response inhibitory capacity.
doi:10.1523/JNEUROSCI.0312-09.2009
PMCID: PMC4263250  PMID: 19420270
cognitive disorganisation; executive function; inhibition; monkey; attention
16.  Slit2, a Branching–Arborization Factor for Sensory Axons in the Mammalian CNS 
Axons that carry information from the sensory periphery first elongate unbranched and form precisely ordered tracts within the CNS. Later, they begin collateralizing into their proper targets and form terminal arbors. Target-derived factors that govern sensory axon elongation and branching–arborization are not well understood. Here we report that Slit2 is a major player in branching–arborization of central trigeminal axons in the brainstem. Embryonic trigeminal axons initially develop unbranched as they form the trigeminal tract within the lateral brainstem; later, they emit collateral branches into the brainstem trigeminal nuclei and form terminal arbors therein. In whole-mount explant cultures of this pathway, embryonic day 15 (E15) rat central trigeminal axons retain their unbranched growth within the tract, whereas E17 trigeminal axons show branching and arborization in the brainstem trigeminal nuclei, much like that seen in vivo. Similar observations were made in E13 and E15 mouse embryos. We cocultured Slit2-expressing tissues or cells with the whole-mount explant cultures of the central trigeminal pathway derived from embryonic rats or mice. When central trigeminal axons are exposed to ectopic Slit2 during their elongation phase, they show robust and premature branching and arborization. Blocking available Slit2 reverses this effect on axon growth. Spatiotemporal expression of Slit2 and Robo receptor mRNAs within the brainstem trigeminal nuclei and the trigeminal ganglion during elongation and branching–arborization further corroborates our experimental results.
PMCID: PMC4260804  PMID: 12040061
Slits; Robos; trigeminal ganglion; trigeminal system; choroid plexus; explant cocultures; axon branching; axon arborization
17.  Suppressing sensorimotor activity modulates the discrimination of auditory emotions but not speaker identity 
Our ability to recognise the emotions of others is a crucial feature of human social cognition. Functional neuroimaging studies indicate that activity in sensorimotor cortices is evoked during the perception of emotion. In the visual domain, right somatosensory cortex activity has been shown to be critical for facial emotion recognition. However, the importance of sensorimotor representations in modalities outside of vision remains unknown. Here we use continuous theta-burst transcranial magnetic stimulation (cTBS) to investigate whether neural activity in the right postcentral gyrus (rPoG) and right lateral premotor cortex (rPM) is involved in non-verbal auditory emotion recognition. Three groups of participants completed same-different tasks on auditory stimuli, discriminating between either the emotion expressed or the speakers’ identities, prior to and following cTBS targeted at rPoG, rPM or the vertex (control site). A task-selective deficit in auditory emotion discrimination was observed. Stimulation to rPoG and rPM resulted in a disruption of participants’ abilities to discriminate emotion, but not identity, from vocal signals. These findings suggest that sensorimotor activity may be a modality independent mechanism which aids emotion discrimination.
doi:10.1523/JNEUROSCI.0786-10.2010
PMCID: PMC4246058  PMID: 20943896
sensorimotor; auditory; emotion; identity; transcranial magnetic stimulation; premotor
18.  Relationships between the Firing of Identified Striatal Interneurons and Spontaneous and Driven Cortical Activities In Vivo 
The striatum is comprised of medium-sized spiny projection neurons (MSNs) and several types of interneuron, and receives massive glutamatergic input from the cerebral cortex. Understanding of striatal function requires definition of the electrophysiological properties of neurochemically identified interneurons sampled in the same context of ongoing cortical activity in vivo. To address this, we recorded the firing of cholinergic interneurons (expressing choline acetyltransferase; ChAT) and GABAergic interneurons expressing parvalbumin (PV) or nitric oxide synthase (NOS), as well as MSNs, in anesthetized rats during cortically defined brain states. Depending on the cortical state, these interneurons were partly distinguished from each other, and MSNs, on the basis of firing rate and/or pattern. During slow-wave activity (SWA), ChAT+ interneurons, and some PV+ and NOS+ interneurons, were tonically active; NOS+ interneurons fired prominent bursts but, contrary to investigations in vitro, these were not typical low-threshold spike bursts. Identified MSNs, and other PV+ and NOS+ interneurons, were phasically active. Contrasting with ChAT+ interneurons, whose firing showed poor brain state dependency, PV+ and NOS+ interneurons displayed robust firing increases and decreases, respectively, upon spontaneous or driven transitions from SWA to cortical activation. The firing of most neurons was phase locked to cortical slow oscillations, but only PV+ and ChAT+ interneurons also fired in time with cortical spindle and gamma oscillations. Complementing this diverse temporal coupling, each interneuron type exhibited distinct responses to cortical stimulation. Thus, these striatal interneuron types have distinct temporal signatures in vivo, including relationships to spontaneous and driven cortical activities, which likely underpin their specialized contributions to striatal microcircuit function.
doi:10.1523/JNEUROSCI.2440-12.2012
PMCID: PMC4242971  PMID: 22993438
19.  Parkinsonian Beta Oscillations in the External Globus Pallidus and Their Relationship with Subthalamic Nucleus Activity 
Inappropriately synchronized beta (β) oscillations (15–30 Hz) in the subthalamic nucleus (STN) accompany movement difficulties in idiopathic Parkinson’s disease (PD). The cellular and network substrates underlying these exaggerated β oscillations are unknown but activity in the external globus pallidus (GP), which forms a candidate pacemaker network with STN, might be of particular importance. Using a clinically relevant rat model of PD, we demonstrate that oscillatory activity in GP neuronal networks becomes excessively and selectively synchronized at β frequencies in a spatially widespread and brain state-dependent manner after lesion of dopamine neurons. Although synchronization of GP unit activity increased by almost 100-fold during β oscillations, the mean firing rate of GP neurons decreased compared with controls. Importantly, in parkinsonian animals, two main types of GP neuron were identified according to their distinct and inversely related firing rates and patterns. Moreover, neurons of the same type tended to fire together, with small phase differences, whereas different types of neuron tended not to do so. This functional dichotomy in temporal coupling persisted across extreme brain states, suggesting that maladaptive interactions are dominated by hard wiring. Finally, the precisely timed discharges of GP and STN neurons indicated that rhythmic sequences of recurrent excitation and inhibition in the STN-GP network, and lateral inhibition between GP neurons, could actively support abnormal β oscillations. We propose that GP neurons, by virtue of their spatiotemporal synchronization, widespread axon collaterals and feed-back/feed-forward mechanisms, are well placed to orchestrate and propagate exaggerated β oscillations throughout the entire basal ganglia in PD.
doi:10.1523/JNEUROSCI.4199-08.2008
PMCID: PMC4243385  PMID: 19109506
globus pallidus; subthalamic nucleus; basal ganglia; Parkinson’s disease; dopamine; 6-hydroxydopamine
20.  Double dissociation of the requirement for GluN2B- and GluN2A-containing NMDA receptors in the destabilization and restabilization of a reconsolidating memory 
Signaling at NMDA receptors (NMDARs) is known to be important for memory reconsolidation, but while most studies show that NMDAR antagonists prevent memory restabilization and produce amnesia, others have shown that GluN2B-selective NMDAR antagonists prevent memory destabilization, protecting the memory. These apparently paradoxical, conflicting data provide an opportunity to define more precisely the requirement for different NMDAR subtypes in the mechanisms underlying memory reconsolidation, and to further understand the contribution of glutamatergic signaling to this process. Here, using rats with fully consolidated pavlovian auditory fear memories, we demonstrate a double dissociation in the requirement for GluN2B-containing and GluN2A-containing NMDARs within the basolateral amygdala in the memory destabilization and restabilization processes, respectively. We further show a double dissociation in the mechanisms underlying memory retrieval and memory destabilization, since AMPAR antagonism prevented memory retrieval while still allowing the destabilization process to occur. These data demonstrate that glutamatergic signaling mechanisms within the basolateral amygdala differentially and dissociably mediate the retrieval, destabilization and restabilization of previously consolidated fear memories.
doi:10.1523/JNEUROSCI.3273-12.2013
PMCID: PMC4241020  PMID: 23325248
21.  Free energy, precision and learning: the role of cholinergic neuromodulation 
Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that acetylcholine enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimising the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore – using dynamic causal modelling – we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that acetylcholine adaptively enhances sensory precision by boosting bottom-up signalling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty.
doi:10.1523/JNEUROSCI.4255-12.2013
PMCID: PMC4235126  PMID: 23658161
Free Energy Principle; Predictive Coding; Neuromodulation; Acetylcholine; Galantamine; Oddball Response; Precision; Dynamic Causal Modelling
22.  Temporal expectation improves the quality of sensory information 
It is increasingly clear that we extract patterns of temporal regularity between events to optimize information processing. Whereas some of the mechanisms for facilitating action preparation and execution have been well documented, much less is understood about whether and how temporal expectations influence visual perception. We used a psychophysical paradigm and computational modeling to investigate the mechanisms by which temporal expectation can modulate visual perception. Visual targets appeared in a stream of noise-patches separated by a fixed (400-ms regular condition) or jittered (200/300/400/500/600-ms irregular condition) intervals. Targets were visual gratings tilted 45° clockwise or counter-clockwise, presented at one of seven contrast levels. Human observers were required to perform an orientation discrimination (i.e. left or right). Psychometric functions for contrast sensitivity fitted for the regular and irregular conditions indicated that temporal expectation modulates perceptual processing by enhancing the contrast sensitivity of visual targets. This increase in the signal strength was accompanied by a reduction in reaction times. A diffusion model indicated that rhythmic temporal expectation enhanced the signal-to-noise gain of the sensory evidence upon which decisions were made. These effects support the idea that attentional focus can entrain to the temporal structure of external events to optimize the processing of relevant sensory information.
doi:10.1523/JNEUROSCI.0804-12.2012
PMCID: PMC4235252  PMID: 22699922
23.  Alpha oscillations related to anticipatory attention follow temporal expectations 
Temporal expectations have been shown to enhance visual analysis of task-relevant events, especially when these are coupled with spatial expectations. Oscillatory brain activity, particularly in the alpha band, has been implicated in regulating excitability in visual areas as a function of anticipatory spatial attention. Here we asked whether temporal expectations derived from regular, rhythmic events can modulate ongoing oscillatory alpha-band activity, so that the changes in cortical excitability are focused over the time intervals at which target events are expected. The task we used involved making a perceptual discrimination about a small target stimulus that reappeared from ‘behind’ a peripheral occluding band. Temporal expectations were manipulated by the regular, rhythmic versus irregular, arrhythmic approach of the stimulus toward the occluding band. Alpha-band activity was measured during the occlusion period, in which no stimulus was presented, but target reappearance was anticipated in conditions of high versus low temporal expectation. Time-frequency analysis showed that the amplitude of alpha-desynchronisation followed the time course of temporal expectations. Alpha desynchronisation increased rhythmically, peaking just before the expected reappearance of target times. Analysis of the event-related potentials evoked by the subsequent target stimuli showed enhancement of processing at both visual and motor stages. Our findings support a role for oscillations in regulating cortical excitability and suggest a plausible mechanism for biasing perception and action by temporal expectations.
doi:10.1523/JNEUROSCI.3387-11.2011
PMCID: PMC4235253  PMID: 21976492
24.  Dorsally- and ventrally-derived oligodendrocytes have similar electrical properties but myelinate preferred tracts 
In the developing spinal cord most oligodendrocyte precursors (OLPs) arise from the ventral ventricular zone (VZ) under the influence of Sonic Hedgehog but a minority is generated from the dorsal VZ in a Hedgehog-independent manner. In the developing forebrain too, OLPs arise from both the ventral and the dorsal VZ. It is not known whether dorsally- and ventrally- derived oligodendrocyte (OL) lineage cells have different properties. We generated a dual reporter mouse line to color code ventrally- and dorsally-derived OLPs (vOLPs and dOLPs) and their differentiated oligodendrocyte progeny (vOLs and dOLs) for functional studies. We found that ~80% of OL lineage cells in the postnatal spinal cord and ~20% in the corpus callosum are ventrally-derived. In both spinal cord and corpus callosum, vOLPs and dOLPs had indistinguishable electrical properties, as did vOLs and dOLs. However, vOLPs and dOLPs had different migration and settling patterns. In the spinal cord, vOLPs appeared early and spread uniformly throughout the cord whereas dOLPs arrived later and remained mainly in the dorsal and dorsolateral funiculi. During adulthood, corticospinal and rubrospinal tracts became myelinated mainly by dOLs, even though vOLs dominated these tracts during early postnatal life. Thus, dOLPs are electrically similar to vOLPs but appear to out-compete them for dorsal axons.
doi:10.1523/JNEUROSCI.6474-10.2011
PMCID: PMC4227601  PMID: 21543611
myelin; spinal cord; development; corticospinal tract; electrophysiology; transgenic mice; Sox10; GFP; tdTomato
25.  Ultra-fast population encoding by cortical neurons 
The processing speed of the brain depends on the ability of neurons to rapidly relay input changes. Prior theoretical and experimental studies of the time scale of population firing rate responses arrived at controversial conclusions, some advocating an ultra-fast response scale while others arguing for an inherent disadvantage of mean encoded signals for rapid detection of the stimulus onset. Here we assessed the time scale of population firing rate responses of neocortical neurons in experiments performed in the time domain and the frequency domain in vitro and in vivo. We show that populations of neocortical neurons can alter their firing rate within 1 millisecond in response to somatically delivered weak current signals presented on a fluctuating background. Signals with amplitudes of miniature postsynaptic currents can be robustly and rapidly detected in the population firing. We further show that population firing rate of neocortical neurons in vitro and in vivo can reliably encode weak signals varying at frequencies up to ~200–300 Hz, or ~50 times faster than the firing rate of individual neurons. These results provide coherent evidence for the ultra-fast, millisecond time-scale of cortical population responses. Notably, fast responses to weak stimuli are limited to the mean encoding. Rapid detection of current variance changes requires extraordinarily large signal amplitudes. Our study presents conclusive evidence showing that cortical neurons are capable of rapidly relaying subtle mean current signals. This provides a vital mechanism for the propagation of rate-coded information within and across brain areas.
doi:10.1523/JNEUROSCI.2182-11.2011
PMCID: PMC4225046  PMID: 21865460

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