bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of Excitatory Chloride Conductance in the Determination of the Direction of Traveling Waves in an Olfactory Center
Authors: Watanabe Satoshi , Inoue Tsuyoshi , Kirino Yutaka
Published: April 2018

Traveling waves have been found in the CNS of vertebrates and invertebrates. In the olfactory center [procerebrum (PC)] of the terrestrial slugLimax, periodic waves travel from the apex to the base with a frequency of ∼0.7 Hz. The oscillation and propagation of waves have been thought to be mediated by the mutual connections of bursting neurons in the PC. The direction of the wave is Cl−dependent, because lowering the Cl−concentration in the medium reverses the direction. The bursting neurons have a Cl−channel-coupled glutamate receptor (GluClR), and, using a calcium imaging technique, the receptor was found to be excitatory. Activation of the GluClR with its selective agonist ibotenate resulted in an increased frequency of the oscillatory neural activity recorded as a periodic local field potential. Depletion of cytoplasmic Cl−with Cl−-free saline abolished all of the ibotenate-induced effects. Perforated-patch-clamp recording in single PC neurons revealed a spatial difference in the Cl−-dependent periodic depolarizations in the bursting neurons, with a higher amplitude in the apical region. These results suggest the involvement of excitatory GluClRs in the unidirectional propagation of waves in the PC.
Premotor Neurons Encode Torsional Eye Velocity during Smooth-Pursuit Eye Movements
Authors: Angelaki Dora E. , Dickman J. David
Published: April 2018

Responses to horizontal and vertical ocular pursuit and head and body rotation in multiple planes were recorded in eye movement-sensitive neurons in the rostral vestibular nuclei (VN) of two rhesus monkeys. When tested during pursuit through primary eye position, the majority of the cells preferred either horizontal or vertical target motion. During pursuit of targets that moved horizontally at different vertical eccentricities or vertically at different horizontal eccentricities, eye angular velocity has been shown to include a torsional component the amplitude of which is proportional to half the gaze angle (“half-angle rule” of Listing's law). Approximately half of the neurons, the majority of which were characterized as “vertical” during pursuit through primary position, exhibited significant changes in their response gain and/or phase as a function of gaze eccentricity during pursuit, as if they were also sensitive to torsional eye velocity. Multiple linear regression analysis revealed a significant contribution of torsional eye movement sensitivity to the responsiveness of the cells. These findings suggest that many VN neurons encode three-dimensional angular velocity, rather than the two-dimensional derivative of eye position, during smooth-pursuit eye movements. Although no clear clustering of pursuit preferred-direction vectors along the semicircular canal axes was observed, the sensitivity of VN neurons to torsional eye movements might reflect a preservation of similar premotor coding of visual and vestibular-driven slow eye movements for both lateral-eyed and foveate species.
p38 Mitogen-Activated Protein Kinase Is Activated after a Spinal Nerve Ligation in Spinal Cord Microglia and Dorsal Root Ganglion Neurons and Contributes to the Generation of Neuropathic Pain
Authors: Jin Shan-Xue , Zhuang Zhi-Ye , Woolf Clifford J. , Ji Ru-Rong
Published: April 2018

The possible involvement of p38 mitogen-activated protein kinase activation in spinal cord and dorsal root ganglion (DRG) cells in the development of peripheral neuropathic pain has been explored. Ligation of the L5 spinal nerve (SNL) on one side in adult rats produces an early onset and long-lasting mechanical allodynia. This lesion results in activation of p38 in the L5 segment of the spinal cord, most prominently in the ipsilateral dorsal horn, starting soon after the lesion (<1 d) and persisting for >3 weeks. The activated p38 in the spinal cord is restricted entirely to microglia; phospho-p38 colocalizes only with the microglial marker OX-42 and not with either the neuronal marker neuronal-specific nuclear protein or the astrocyte marker GFAP. In contrast, SNL induces a delayed (>3 d) activation of p38 in the L5 DRG that occurs predominantly in neurons. Continuous injection of the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) via the intrathecal route, starting before the SNL surgery, reduces SNL-induced mechanical allodynia from day 1 to day 10, with maximal effects at early time points. Post-treatment with SB203580 starting on day 1 or on day 10 after surgery also reduces established mechanical allodynia. Because the reduction in neuropathic pain by p38 inhibition occurs before the appearance of p38 activation in DRG neurons, p38 activation in spinal cord microglia is likely to have a substantial role in the earliest phase of neuropathic pain. Coactivation of p38 in DRG neurons and spinal microglia may contribute to later phases of neuropathic pain.
In VivoWhole-Cell Recording of Odor-Evoked Synaptic Transmission in the Rat Olfactory Bulb
Authors: Cang Jianhua , Isaacson Jeffry S.
Published: April 2018

One of the first steps in the coding of olfactory information is the transformation of synaptic input to action potential firing in mitral and tufted (M/T) cells of the mammalian olfactory bulb. However, little is known regarding the synaptic mechanisms underlying this processin vivo. In this study, we examined odor-evoked response patterns of M/T and granule cells using whole-cell recording in anesthetized, freely breathing rats. We find that odor-evoked excitatory responses in M/T cells typically consist of bursts of action potentials coupled to the ∼2 Hz respiration rhythm. Odor-evoked, rhythmic M/T cell excitation is reliable during odor presentation (2–4 sec); in contrast, both excitatory responses of granule cells and M/T cell lateral inhibition adapt quickly after the first respiration cycle in the presence of odorants. We also find that the amplitude and initial slope of odor-evoked synaptic excitation play an important role in regulating the timing of M/T cell spikes. Furthermore, differences in odor concentration alter the shape of odor-evoked excitatory synaptic responses, the latency of M/T cell spikes, and the timing of M/T cell lateral inhibition.
A Functional Gamma-Band Defined by Stimulus-Dependent Synchronization in Area 18 of Awake Behaving Cats
Authors: Siegel Markus , König Peter
Published: April 2018

During the past decade, numerous studies have demonstrated stimulus-specific synchronization of neuronal activity in the γ-frequency range. However, it appears that the different analyses are based on widely different assumptions about which frequency range to investigate. Therefore, the term “γ-synchronization” refers to an inhomogeneous spectrum of definitions and corresponding frequency bands. Moreover, most studies have been performed in anesthetized animals or in awake animals by use of fixation paradigms. Thus, it is difficult to relate these results to alert animals behaving under natural conditions. Here, we investigate stimulus specific synchronization in primary visual cortex of awake cats in a tracking paradigm. We record local field potentials and multiunit activity simultaneously from multiple electrodes. (1) We demonstrate that visual stimulation induces neuronal synchronization in a broad frequency range reaching well above 100 Hz. (2) We derive a functional γ-band based on an objective criterion: We show that synchronization of neuronal activity is optimally orientation-tuned when a broad frequency band is considered. This band starts above 40 Hz, a frequency that is typically related to the term γ-synchronization, and extends to very high frequencies. Interestingly, the frequency of maximum synchronization is different from the frequency at which synchronization is most stimulus specific. (3) We demonstrate synchronization of neuronal activity in a distinct low-frequency band with different properties suggesting separate functional roles of low- and high-frequency synchronization.
Error Monitoring Using External Feedback: Specific Roles of the Habenular Complex, the Reward System, and the Cingulate Motor Area Revealed by Functional Magnetic Resonance Imaging
Authors: Ullsperger Markus , von Cramon D. Yves
Published: April 2018

The dopaminergic system has been shown to be involved in the processing of rewarding stimuli, specifically of errors in reward prediction, in animal studies as well as in recent neuroimaging studies in humans. Furthermore, a specific role of dopamine in the human homolog of the rostral cingulate motor area (rCMA) was proposed in a recent model of error detection. Negative feedback as well as self-detected errors elicit a negative event-related brain potential probably generated in the rCMA. We performed two experiments using functional magnetic resonance imaging to investigate the brain activity related to negative and positive feedback in a dynamically adaptive motion prediction task. Whereas positive feedback raised hemodynamic activity in the ventral striatum (nucleus accumbens), negative feedback activated the rCMA, the inferior anterior insula, and the epithalamus (habenular complex). These data demonstrate the role of the habenular complex in the control of the human reward system, a function previously hypothesized on the basis of animal research. The rCMA reacted only to errors with negative feedback but not to errors without feedback, which ruled out an influence of response conflict or uncertainty on its role in error detection by external signals.
Selective Hippocampal Lesions Do Not Increase Adrenocortical Activity
Authors: Tuvnes Frode A. , Steffenach Hill-Aina , Murison Robert , Moser May-Britt , Moser Edvard I.
Published: April 2018

It has been proposed that the hippocampus exerts a tonic inhibitory influence on the hypothalamic–pituitary–adrenal (HPA) stress axis. This claim rests, in particular, on the upregulation of corticosterone secretion and other measures of HPA activity after nonselective lesions of the hippocampal formation. We measured plasma corticosterone concentrations after selective neurotoxic damage to the hippocampus and the subiculum in rats. Concentrations were estimated during rest in the rat's home cage and at several time points after varying degrees of stress. Lesions of the hippocampus did not increase the concentration of corticosterone relative to control rats in any condition. Temporary inactivation of the hippocampus or the ventral subiculum by infusion of the GABAAreceptor agonist muscimol also failed to induce hypersecretion, although hippocampal infusions did impair spatial memory. These results suggest that the hippocampus is not necessary for tonic inhibition of adrenocortical activity and imply that the HPA axis receives efficient negative feedback inhibition from other brain systems too.
Social Influences on the Arginine Vasotocin System Are Independent of Gonads in a Sex-Changing Fish
Authors: Semsar Katharine , Godwin John
Published: April 2018

Many neuropeptide systems subserving sex-typical behavior are dependent on sex steroids for both their organization early in life and activation during maturity. The arginine vasopressin/vasotocin (AVP/AVT) system is strongly androgen dependent in many species and critically mediates responses to sociosexual stimuli. The bluehead wrasse is a teleost fish that exhibits a female-to-male sex change in response to social cues, and neither the development nor the maintenance of male-typical behavior depends on the presence of gonads. To examine social and gonadal inputs on the AVP/AVT system in the preoptic area (POA) of the hypothalamus, we conducted three field experiments. In the first experiment, we found that AVT mRNA abundance is higher in sex-changing females that attain social dominance and display dominant male behavior than in subordinate females, regardless of whether the dominant females were intact or ovariectomized. However, AVT-immunoreactive (IR) soma size in the gigantocellular POA (gPOA), but not in the magnocellular or parvocellular POA, increased only when females were displaying both dominant male behavior and had developed testes. In the second experiment, castration of dominant terminal-phase males had no effect on AVT mRNA abundance or any behavior we measured but did increase gPOA AVT-IR soma size compared with sham-operated controls. In the third experiment, 11-ketotestosterone implants in socially subordinate, ovariectomized females had no effect on either AVT mRNA abundance or AVT-IR soma size compared with controls. These results demonstrate that the AVT neural phenotype in the bluehead wrasse can be strongly influenced by social status, and that these social influences can be manifested independent of gonads.
Brainstem Substrates of Sympatho-Motor Circuitry Identified Using Trans-Synaptic Tracing with Pseudorabies Virus Recombinants
Authors: Kerman Ilan A. , Enquist Lynn W. , Watson Stanley J. , Yates Bill J.
Published: April 2018

Previous physiological investigations have suggested the existence of a neural circuit that coordinates activation of motor and autonomic efferents before or at the onset of exercise. Traditionally these circuits have been postulated to involve forebrain areas. However, overlapping populations of medullary reticular formation neurons that participate in motor or autonomic control have been described previously, suggesting that individual pontomedullary reticular formation neurons may coordinate both motor and autonomic responses. We tested this hypothesis by conducting transneuronal retrograde tracing of motor and sympathetic nervous system pathways in rats using recombinant strains of pseudorabies virus (PRV). A PRV strain expressing the green fluorescent protein (PRV-152) was injected into the left gastrocnemius muscle, which was surgically sympathectomized, whereas another recombinant (PRV-BaBlu) was injected into the left adrenal gland. Immunofluorescence methods using monospecific antisera and distinct fluorophores identified neurons infected with one or both of the recombinants. Brainstem neurons coinfected with both PRV recombinants, which presumably had collateralized projections to both adrenal sympathetic preganglionic neurons and gastrocnemius motoneurons, were observed in several areas of the pontomedullary reticular formation. The largest number of such neurons was located in the rostral ventromedial medulla within the ventral gigantocellular nucleus, gigantocellular nucleus pars alpha, raphe obscurus, and raphe magnus. These neurons are candidates for relaying central command signals to the spinal cord.
Frequency-Specific Interaural Level Difference Tuning Predicts Spatial Response Patterns of Space-Specific Neurons in the Barn Owl Inferior Colliculus
Authors: Spezio Michael L. , Takahashi Terry T.
Published: April 2018

Space-specific neurons in the barn owl's inferior colliculus have spatial receptive fields (RFs) because of sensitivity to interaural time difference and frequency-specific interaural level difference (ILD). These neurons are assumed to be tuned to the frequency-specific ILDs occurring at their spatial RFs, but attempts to assess this tuning with traditional narrowband stimuli have had limited success. Indeed, tuning assessed in this manner, when processed via a linear model of spectral integration, typically explains only approximately half the variance in spatial response patterns. Here we report our findings that frequency-specific ILD tuning of space-specific neurons, when assessed from responses to broadband stimuli, predicted nearly 75% of the variance in spatial responses, using a linear model of spectral integration (p< 0.0001;n= 97 neurons). Furthermore, when we tested neurons using only those frequencies we found to be spatially relevant, we saw that their responses were similar to those elicited by broadband stimuli. When we used frequencies not identified as spatially relevant, such similarity was lacking. Furthermore, spectral components that elicited high firing rates when presented as narrowband stimuli were found in several cases to be irrelevant for or detrimental to the definition of spatial RFs. Thus, neurons achieved sharp spatial tuning by selecting for ILDs of a subset of spectral components in noise, some of which were not identified using narrowband stimuli.
Corollary Discharge Inhibition of Ascending Auditory Neurons in the Stridulating Cricket
Authors: Poulet James F. A. , Hedwig Berthold
Published: April 2018

Acoustically communicating animals are able to process external acoustic stimuli despite generating intense sounds during vocalization. We have examined how the crickets' ascending auditory pathway copes with self-generated, intense auditory signals (chirps) during singing (stridulation). We made intracellular recordings from two identified ascending auditory interneurons, ascending neuron 1 (AN1) and ascending neuron 2 (AN2), during pharmacologically elicited sonorous (two-winged), silent (one-winged), and fictive (isolated CNS) stridulation.

During sonorous chirps, AN1 responded with bursts of spikes, whereas AN2 was inhibited and rarely spiked. Low-amplitude hyperpolarizing potentials were recorded in AN1 and AN2 during silent chirps. The potentials were also present during fictive chirps. Therefore, they were the result of a centrally generated corollary discharge from the stridulatory motor network. The spiking response of AN1 and AN2 to acoustic stimuli was inhibited during silent and fictive chirps. The maximum period of inhibition occurred in phase with the maximum spiking response to self-generated sound in a sonorously stridulating cricket. In some experiments (30%) depolarizing potentials were recorded during silent chirps. Reafferent feedback elicited by wing movement was probably responsible for the depolarizing potentials.

In addition, two other sources of inhibition were present in AN1: (1) IPSPs were elicited by stimulation with 12.5 kHz stimuli and (2) a long-lasting hyperpolarization followed spiking responses to 4.5 kHz stimuli. The hyperpolarization desensitized the response of AN1 to subsequent quieter stimuli. Therefore, the corollary discharge will reduce desensitization by suppressing the response of AN1 to self-generated sounds.
Human θ Oscillations Related to Sensorimotor Integration and Spatial Learning
Authors: Caplan Jeremy B. , Madsen Joseph R. , Schulze-Bonhage Andreas , Aschenbrenner-Scheibe Richard , Newman Ehren L. , Kahana Michael J.
Published: April 2018

θ oscillations in the rat hippocampus have been implicated in sensorimotor integration (Bland, 1986), especially during exploratory and wayfinding behavior. We propose that human cortical θ activity coordinates sensory information with a motor plan to guide wayfinding behavior to known goal locations. To test this hypothesis, we analyzed invasive recordings from epileptic patients while they performed a spatially immersive, virtual taxi driver task. Consistent with this hypothesis, we found θ oscillations during both exploratory search and goal-seeking behavior and, in particular, during virtual movement, when sensory information and motor planning were both in flux, compared with periods of self-initiated stillness. θ oscillations had different topographic and spectral characteristics during searching than during goal-seeking, suggesting that different cortical networks exhibit θ depending on which cognitive functions are driving behavior (spatial learning during exploration vs orienting to a learned representation during goal-seeking). In contrast, oscillations in the β band appeared to be related to simple motor planning, likely a variant of the Rolandic μ rhythm. These findings suggest that human cortical θ oscillations act to coordinate sensory and motor brain activity in various brain regions to facilitate exploratory learning and navigational planning.
Fatigue and Paradoxical Enhancement of Heat Response in C-Fiber Nociceptors from Cross-Modal Excitation
Authors: Peng Yuan B. , Ringkamp Matthias , Meyer Richard A. , Campbell James N.
Published: April 2018

Fatigue refers to the decrement of response seen with repeated stimulation and is a prominent attribute of nociceptors. Whether fatigue in nociceptors involves transduction, spike initiation, or conduction mechanisms is unknown. We investigated systematically how electrical, mechanical, and heat conditioning stimuli (eCS, mCS, hCS) affected the subsequent response to a test-heat stimulus applied 5 sec later to the receptive field of cutaneous nociceptors. Standard teased-fiber techniques were used to record from mechano–heat-sensitive C-fiber afferents in the anesthetized monkey. The eCS was applied to the nerve trunk, whereas the hCS and mCS were applied to the heat-test site. For the eCS, the number of pulses rather than frequency of stimulation determined the level of fatigue. Fatigue varied inversely with the time interval between the eCS and the test stimulus. For comparable responses from the CS, the magnitude of fatigue was less after the mCS than after the eCS. The mCS (but not the eCS) sometimes evoked a paradoxical increase in response to the test-heat stimulus. Recovery from fatigue was significantly faster after the eCS and mCS than the hCS. The paradoxical enhancement after the mCS probably results from temporal summation of generator potentials produced by mechanical and heat stimulation and suggests that the time constant of the generator potential is on the order of seconds. Concurrent enhancement–fatigue effects may also explain why fatigue was less after the mCS than the eCS. The dependency of recovery from fatigue on the modality of the CS suggests that fatigue results from transduction–spike initiation mechanisms.
Functional Tolerance and Blockade of Long-Term Depression at Synapses in the Nucleus Accumbens after Chronic Cannabinoid Exposure
Authors: Hoffman Alexander F. , Oz Murat , Caulder Tara , Lupica Carl R.
Published: April 2018

The rewarding properties of the psychoactive constituents of marijuana, termed “cannabinoids,” may reflect actions on synaptic transmission in the nucleus accumbens (NAc). Furthermore, long-term changes in these synapses may support the addictive process. Excitatory and inhibitory synapses are acutely inhibited by cannabinoids in the NAc, and endogenous cannabinoids (endocannabinoids) play a critical role in the expression of long-term depression (LTD) of excitatory cortical afferents in this structure. Because humans often use marijuana for prolonged periods, we examined the impact of long-term cannabinoid exposure on synaptic processes in an animal model. Electrophysiological recordings in rat brain slices containing the NAc were performed after chronic exposure to vehicle solution, Δ9-tetrahydrocannabinol (THC), or the cannabinoid agonistR(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2). Extracellular glutamatergic postsynaptic potentials and whole-cell GABAergic IPSCs were concentration-dependently inhibited by WIN55,212-2 in slices from naive or vehicle-treated animals. However, the sensitivity to WIN55,212-2 was diminished in chronic agonist-treated animals. In addition, cross-tolerance to the inhibitory effect of the μ-opioid agonist Tyr-d-Ala2,N-CH3-Phe4,Gly-ol-enkephalin was observed. Endocannabinoid-mediated LTD was initiated via electrical stimulation (5 min, 10 Hz) of glutamatergic afferents to the NAc and was completely blocked by the cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] in vehicle-treated animals. LTD was not observed in brain slices from rats chronically treated with Δ9-THC or WIN55,212-2. These data demonstrate that long-term exposure to the active ingredient of marijuana blocks synaptic plasticity in the NAc and reduces the sensitivity of GABAergic and glutamatergic synapses to both cannabinoids and opioids.
Generalization of Object Manipulation Skills Learned without Limb Motion
Authors: Mah Christopher D. , Mussa-Ivaldi Ferdinando A.
Published: April 2018

Recent work suggests that human subjects may learn mappings between object motion and exerted torque during manipulation of freely pivoting or unstable objects. In the present work, we studied an object manipulation task involving no arm movement to determine how subjects internally represent the force—motion relationship of an object during a skilled manipulation task. Human subjects learned to balance a simulated inverted pendulum. The simulation was controlled by pressing on a fixed force sensor, and applied forces resulted in motion of the simulated pendulum on a computer screen according to its equation of motion. Each subject initially learned the task in one arm posture and was tested 1 d later in a new arm posture. In one test condition, the effects of arm torque were matched to the original task, and in the other test condition, the simulation was unchanged. The pattern of skill transfer to different arm postures suggested that subjects had learned joint torque responses rather than a general model of the object interface forces. A second experiment showed that the advantage of training with matched arm torques was object specific, because torque-matched training on a tracking task involving similar forces was not a substitute for training in the balancing task.
Synaptic Activation of Presynaptic Glutamate Transporter Currents in Nerve Terminals
Authors: Palmer Mary J. , Taschenberger Holger , Hull Court , Tremere Liisa , von Gersdorff Henrique
Published: April 2018

Glutamate uptake by high-affinity transporters is responsible for limiting the activation of postsynaptic receptors and maintaining low levels of ambient glutamate. The reuptake process generates membrane currents, which can be activated by synaptically released glutamate in glial cells and some postsynaptic neurons. However, less is known about presynaptic transporter currents because the small size of synaptic boutons precludes direct recordings. Here, we have recorded from two giant nerve terminals: bipolar cell synaptic terminals in goldfish retina and the calyx of Held in rat auditory brainstem. Exocytosis was evoked by brief depolarizations and measured as an increase in membrane capacitance. In isolated bipolar cell terminals, exocytosis was associated with an anion (NO3-or Cl-) current. The current peaked 2.8 msec after the start of the depolarization and decayed with a mean time constant of 8.5 msec. It was inhibited by the nontransportable glutamate transporter antagonistsc-threo-β-benzyloxyaspartate (TBOA) but was insensitive to the GLT1/EAAT2 subtype-selective antagonist dihydrokainate and was affected by extracellular pH buffering. A TBOA-sensitive anion current was also evoked by application of exogenous glutamate to bipolar cell terminals. The large single-channel conductance, derived from noise analysis, and previous immunolocalization studies suggest that synaptically released glutamate activates EAAT5-type transporters in bipolar cell terminals. In contrast, neither exocytosis nor exogenous glutamate evoked a transporter current in the calyx of Held. Glutamate transporter currents with rapid kinetics are therefore identified and characterized in bipolar cell terminals, providing a valuable system for investigating the function and modulation of presynaptic glutamate transporters.
The Position of the Fourth Segment of Domain 4 Determines Status of the Inactivation Gate in Na+Channels
Authors: Yang Ya-Chin , Kuo Chung-Chin
Published: April 2018

The fourth segment of domain 4 (S4/D4) in Na+channels is a voltage sensor especially implicated in channel inactivation. Although there has been evidence that S4/D4 moves externally during membrane depolarization, whether (and if so, how) the movement leads to conformational changes of the inactivation gate remains unknown. We added a positive charge just external to the outermost charged residue in S4/D4 by point mutations of residue F1625 (i.e., F1625R and F1625K). The inactivation curves as well as the kinetics of recovery from inactivation in these mutant channels are split into two components, one happening with and the other without channel activation/deactivation. This is as if the “extra” positive charge induces new intermediate positions of S4/D4 and consequently new intermediate inactivation states uncoupled from channel activation/deactivation. The qualitatively similar but quantitatively very different findings between the F1625R and F1625K mutants further suggest a significantly different effect on the inactivation gate by a slight difference in the localization of the positive charge. On the other hand, neutral mutations of residue F1625 do not induce new inactivation states but shift the voltage dependence of different inactivation parameters in the voltage axis, as if only the relative tendency of S4/D4 to stay in its original outermost and innermost positions is altered. We conclude that S4/D4 movement not only decisively but also delicately controls the inactivation gate. Electrostatic interaction between the top charges of S4/D4 and the corresponding countercharges may play an essential role in the determination of S4/D4 position and therefore the inactivation status of the Na+channel.
Regulation of Natural Cell Death in Dopaminergic Neurons of the Substantia Nigra by Striatal Glial Cell Line-Derived Neurotrophic FactorIn Vivo
Authors: Oo Tinmarla Frances , Kholodilov Nikolai , Burke Robert E.
Published: April 2018

Dopamine (DA) neurons of the substantia nigra undergo a developmental cell death event that is biphasic, with peaks just after birth and at postnatal day 14. As envisioned by neurotrophic theory, this cell death is likely to be regulated by target interactions because it is augmented by their disruption. However, the nature of the trophic molecules mediating this regulation are unknown. We showedin vitrothat glial cell line-derived neurotrophic factor (GDNF) is able to suppress apoptotic death in DA neurons in postnatal primary culture. We now demonstratein vivothat administration of GDNF into the striatal target is able to suppress apoptosis. Consistent with a possible physiologic role for endogenous striatal GDNF in regulating this event, two anti-GDNF neutralizing antibodies augment cell death. These antibodies augment cell death only during the first (immediately postnatal) phase of the biphasic death event. We conclude that GDNF is the leading candidate for a target-derived neurotrophic factor for the regulation of the early phase of natural cell death in DA neurons.
Aberrant Development of Motor Axons and Neuromuscular Synapses inMyoD-NullMice
Authors: Wang Zuo-Zhong , Washabaugh Charles H. , Yao Yun , Wang Jun-Mei , Zhang Lili , Ontell Martin P. , Watkins Simon C. , Rudnicki Michael A. , Ontell Marcia
Published: April 2018

Myogenic regulatory factors (MRFs), muscle-specific transcription factors, are implicated in the activity-dependent regulation of nicotinic acetylcholine receptor (AChR) subunit genes. Here we show, with immunohistochemistry, Western blotting, and electron microscopy that MyoD, a member of the MRF family, also plays a role in fetal synapse formation. In the diaphragm of 14.5 d gestation (E14.5) wild-type andMyoD-/-mice, AChR clusters (the formation of which is under a muscle intrinsic program) are confined to a centrally located endplate zone. This distribution persists in wild-type adult muscles. However, beginning at E15.5 and extending to the adult, innervated AChR clusters are distributed all over the diaphragm ofMyoD-/-mice, extending as far as the insertion of the diaphragm into the ribs. In wild-type muscle, motor axons terminate on clusters adjacent to the main intramuscular nerve; inMyoD-/-muscle, axonal bundles form extensive secondary branches that terminate on the widely distributed clusters. The number of AChR clusters on adultMyoD-/-and wild-type diaphram muscles is similar. Junctional fold density is reduced atMyoD-/-endplates, and the transition from the fetal (α, β, γ, δ) to adult-type (α, β, δ, ϵ) AChRs is markedly delayed. However,MyoD-/-mice assemble a complex postsynaptic apparatus that includes muscle-specific kinase (MuSK), rapsyn, erbB, and utrophin.
Transforming Growth Factor-βs Are Essential for the Development of Midbrain Dopaminergic NeuronsIn VitroandIn Vivo
Authors: Farkas Lilla M. , Dünker Nicole , Roussa Eleni , Unsicker Klaus , Krieglstein Kerstin
Published: April 2018

Development of midbrain dopaminergic neurons is known to depend on inductive signals derived from the ventral midline, including Sonic hedgehog (Shh) as one of the identified molecules. Here we show that in addition to Shh, transforming growth factor (TGF)-β is required for both induction and survival of ventrally located midbrain dopaminergic neurons. Like Shh, TGF-β is expressed in early embryonic structures such as notochord and floor plate, as well as in the area where mibrain dopaminergic neurons are developing. Treatment of cells dissociated from the rat embryonic day (E) 12 mibrain floor with TGF-β significantly increases the number of tyrosine hydroxylase (TH)-positive dopaminergic neurons within 24 hr. Neutralization of TGF-βin vitrocompletely abolishes the induction of dopaminergic neurons. In the absence of TGF-β, Shh cannot induce TH-positive neurons, and vice versa, neutralizing endogenous Shh abolishes the capacity of TGF-β to induce dopaminergic neuronsin vitro. Furthermore, neutralization of TGF-βin vivoduring chick E2–7 but not E4–7 resulted in a significant reduction in TH-positive neurons in the ventral midbrain floor but not in the locus coeruleus or diencephalon, which suggests that the TGF-β is required for the induction of mesencephalic dopaminergic neurons with a critical time period at E2/E3. Furthermore, neutralization of TGF-β between E6 and 10, a time period during maturation of mesencephalic dopaminergic neurons when no further inductive cues are required, also resulted in a significant loss of dopaminergic neurons, suggesting that TGF-β is required for the promotion of survival of ventral midbrain dopaminergic neurons as well. Together, our results identify TGF-β as an essential mediator for the induction and maintenance of midbrain dopaminergic neurons.
Bone Marrow-Derived Cells that Populate the Adult Mouse Brain Preserve Their Hematopoietic Identity
Authors: Vallières Luc , Sawchenko Paul E.
Published: April 2018

Cytogenesis in the adult brain can result from the recruitment of circulating precursors, but the proposal that some such cells transdifferentiate into neural elements is controversial. We have reinvestigated this issue by following the phenotypic fate of bone marrow cells expressing the green fluorescent protein transplanted into the systemic circulation of irradiated mice. Thousands of donor-derived cells were detected throughout brains of recipients killed 1–12 months after transplantation, but none displayed neuronal, macroglial, or endothelial characteristics, even after injury. Among those that crossed the endothelium of the cerebral cortex, >99.7% were identified as perivascular macrophages. Newly formed parenchymal microglia were found in significant numbers only in the cerebellum and at injury sites. Therefore, bone marrow does supply the mature brain with new specialized cells; however, mesenchymal precursors neither adopt neural phenotypes nor contribute to cerebral vascular remodeling. This continuous traffic of macrophages across the blood–brain barrier provides a vehicle to introduce therapeutic genes into the nervous system.
Axo-Axonic Structures in the Medial Prefrontal Cortex of the Rat: Reduction by Prenatal Exposure to Cocaine
Authors: Morrow Bret A. , Elsworth John D. , Roth Robert H.
Published: April 2018

The cognitive deficits associated with prenatal exposure to cocaine have been hypothesized to be the results of changes in the anatomy and function of the frontal cortex. In this study, pregnant dams were treated with cocaine (3 mg/kg i.v. twice a day) and the resulting adolescent (postnatal day, ∼45) male offspring were killed for immunocytochemical determination of the total linear measure, number, location, and lengths of inhibitory GABA transporter-1 immunoreactive axo-axonic structures commonly called “candles” or “cartridges” in the medial prefrontal cortex. These inhibitory structures are the axon terminals of GABAergic cells that impinge on the initial axon segments of excitatory pyramidal neurons. We report that prenatal cocaine exposure decreased the number of these inhibitory candles. The greatest reduction of candles was observed in the ventral prelimbic cortex. Additionally, there was a subtle difference in the pattern of distribution of candles, namely the depth of the initial candle in the ventral portions of the prefrontal cortex was greater in rats exposed to prenatal cocaine. However, there was no overt change in the number of cells that were immunoreactive for the calcium-binding protein parvalbumin, an indicator of a subset of GABAergic interneurons that includes axo-axonic chandelier cells. We conclude that exposure to cocainein uterodisrupts the development of the axo-axonic cells in the prefrontal cortex and this disruption could contribute to the cognitive deficits reported with prenatal cocaine exposure.
A Comparison of Primate Prefrontal and Inferior Temporal Cortices during Visual Categorization
Authors: Freedman David J. , Riesenhuber Maximilian , Poggio Tomaso , Miller Earl K.
Published: April 2018

Previous studies have suggested that both the prefrontal cortex (PFC) and inferior temporal cortex (ITC) are involved in high-level visual processing and categorization, but their respective roles are not known. To address this, we trained monkeys to categorize a continuous set of visual stimuli into two categories, “cats” and “dogs.” The stimuli were parametrically generated using a computer graphics morphing system (Sheltonelton, 2000) that allowed precise control over stimulus shape. After training, we recorded neural activity from the PFC and the ITC of monkeys while they performed a category-matching task. We found that the PFC and the ITC play distinct roles in category-based behaviors: the ITC seems more involved in the analysis of currently viewed shapes, whereas the PFC showed stronger category signals, memory effects, and a greater tendency to encode information in terms of its behavioral meaning.
Three-Dimensional Organization of the Recurrent Axon Collateral Network of the Substantia Nigra Pars Reticulata Neurons in the Rat
Authors: Mailly Philippe , Charpier Stéphane , Menetrey Annie , Deniau Jean-Michel
Published: April 2018

The substantia nigra pars reticulata (SNR) constitutes a major output nucleus of the basal ganglia where the final stage of information processing within this system takes place. In this study, using juxtacellular labeling and three-dimensional reconstruction methods, we investigated the spatial organization of the intranigral innervation provided by single GABAergic projection neurons from the sensory-motor subdivision of the rat SNR. Confirming previous observations, most labeled SNR cells were found to possess a local axonal network innervating the pars reticulata and pars compacta (SNC). Within the SNR, axons of these cells were distributed along curved laminas enveloping a dorsolaterally located core, thus mostly respecting the onion-like compartmentalization of this nucleus. Although the axonal projection field mostly remained confined to the dendritic field of the parent neuron, it usually extended beyond its limits in caudal, lateral, and/or dorsal directions. Because SNR cells are GABAergic, this pattern of axonal projection suggests the existence of lateral inhibitory interactions between neurons belonging to the same as well as to adjacent functional subdivisions. Axonal projections of SNR cells to the SNC formed longitudinal bands. These bands partly occupied the SNC region projecting to the striatal sector from which parent SNR cells receive their afferents. These data indicate that SNR cells contribute to an indirect nigrostriatal loop circuit through which the striatum could upregulate its level of dopaminergic transmission via a disinhibition of nigrostriatal neurons. Spatial relationships between elements of this indirect nigrostriatonigral circuit indicate that this circuit operates in both a closed and open loop manner.
Activation of β1-Adrenoceptors Excites Striatal Cholinergic Interneurons through a cAMP-Dependent, Protein Kinase-Independent Pathway
Authors: Pisani A. , Bonsi P. , Centonze D. , Martorana A. , Fusco F. , Sancesario G. , De Persis C. , Bernardi G. , Calabresi P.
Published: April 2018

The role of noradrenergic neurotransmission was analyzed in striatal cholinergic interneurons. Conventional intracellular and whole-cell patch-clamp recordings were made of cholinergic interneurons in rat brain slice preparations. Bath-applied noradrenaline (NA) (1–300 μm) dose-dependently induced both an increase in the spontaneous firing activity and a membrane depolarization of the recorded cells. In voltage-clamped neurons, an inward current was induced by NA. This effect was not prevented by α-adrenoceptor antagonists, whereas it was mimicked by the β-adrenoceptor agonist isoproterenol and blocked by the β1 antagonists propranolol and betaxolol. Interestingly, forskolin, activator of adenylate cyclase, mimicked and occluded the membrane depolarization obtained at saturating doses of both dopamine and NA. Accordingly, SQ22,536, a selective adenylate cyclase inhibitor, reduced the response to NA. Analysis of the reversal potential of the NA-induced current did not provide homogeneous results, indicating the involvement of multiple membrane conductances. Because cAMP is known to modulateIh, the effects of ZD7288, a selective inhibitor ofIhcurrent, were examined on the NA-induced membrane depolarization/inward current. ZD7288 mostly reduced the response to NA. However, both KT-5720 and H-89, selective protein kinase A (PKA) blockers, failed to prevent the excitatory action of NA. Likewise, calphostin C, antagonist of PKC, genistein, inhibitor of tyrosine kinase, and 8-Bromo-cGMP, blocker of PKG, did not affect the response to NA. Finally, double-labeling experiments combining β1-adrenoceptor and choline acetyltransferase immunocytochemistry by means of confocal microscopy revealed a strongβ1-adrenoceptor labeling on cholinergic interneurons. We conclude that NA depolarizes striatal cholinergic interneurons via β1-adrenoceptor activation, through a cAMP-dependent but PKA-independent mechanism.
Acute Remapping within the Motor System Induced by Low-Frequency Repetitive Transcranial Magnetic Stimulation
Authors: Lee Lucy , Siebner Hartwig R. , Rowe James B. , Rizzo Vincenzo , Rothwell John C. , Frackowiak Richard S. J. , Friston Karl J.
Published: April 2018

Repetitive transcranial magnetic stimulation (rTMS) of human primary motor cortex (M1) changes cortical excitability at the site of stimulation and at distant sites without affecting simple motor performance. The aim of this study was to explore how rTMS changes regional excitability and how the motor system compensates for these changes. Using functional brain imaging, activation was mapped at rest and during freely selected finger movements after 30 min of 1 Hz rTMS. rTMS increased synaptic activity in the stimulated left M1and induced widespread changes in activity throughout areas engaged by the task. In particular, movement-related activity in the premotor cortex of the nonstimulated hemisphere increased after 1 Hz rTMS. Analyses of effective connectivity confirmed that the stimulated part of M1became less responsive to input from premotor and mesial motor areas. Conversely, after rTMS our results were consistent with increased coupling between an inferomedial portion of left M1and anterior motor areas. These results are important for three reasons. First, they show changes in motor excitability to central inputs from other cortical areas (as opposed to peripheral or exogenous inputs used in previous studies). Second, they suggest that maintenance of task performance may involve activation of premotor areas contralateral to the site of rTMS, similar to that seen in stroke patients. Third, changes in motor activations at the site of rTMS suggest an rTMS-induced remodeling of motor representations during movement. This remapping may provide a neural substrate for acute compensatory plasticity of the motor system in response to focal lesions such as stroke.
Reversal Frequency inCaenorhabditis elegansRepresents an Integrated Response to the State of the Animal and Its Environment
Authors: Zhao Beibei , Khare Parul , Feldman Lisa , Dent Joseph A.
Published: April 2018

The locomotion ofCaenorhabditis elegansconsists of forward crawling punctuated by spontaneous reversals. To better understand the important variables that affect locomotion, we have described in detail the locomotory behavior ofC. elegansand identified a set of parameters that are sufficient to describe the animal's trajectory. A model of locomotion based on these parameters indicates that reversal frequency plays a central role in locomotion. We found that several variables such as humidity, gravidity, and mechanostimulation influence reversal frequency. Specifically, both gentle and harsh touch can transiently suppress reversal frequency. Thus, reversal behavior is a model for the integration of information from numerous modalities reflecting diverse aspects of the state of an organism.
Genetic Analysis of the Roles of Hh, FGF8, and Nodal Signaling during Catecholaminergic System Development in the Zebrafish Brain
Authors: Holzschuh Jochen , Hauptmann Giselbert , Driever Wolfgang
Published: April 2018

CNS catecholaminergic neurons can be distinguished by their neurotransmitters as dopaminergic or noradrenergic and form in distinct regions at characteristic embryonic stages. This raises the question of whether all catecholaminergic neurons of one transmitter type are specified by the same set of factors. Therefore, we performed genetic analyses to define signaling requirements for the specification of distinct clusters of catecholaminergic neurons in zebrafish. In mutants affecting midbrain– hindbrain boundary (MHB) organizer formation, the earliest ventral diencephalic dopaminergic neurons appear normal. However, after 2 d of development, we observed fewer cells than in wild types, which suggests that the MHB provides proliferation or survival factors rather than specifying ventral diencephalic dopaminergic clusters. In hedgehog (Hh) pathway mutants, the formation of catecholaminergic neurons is affected only in the pretectal cluster. Surprisingly, neither fibroblast growth factor 8 (FGF8) alone nor in combination with Hh signaling is required for specification of early developing dopaminergic neurons. We analyzed the formation of prosomeric territories in the forebrain of Hh and Nodal pathway mutants to determine whether the absence of specific dopaminergic clusters may be caused by early patterning defects ablating corresponding parts of the CNS. In Nodal pathway mutants, ventral diencephalic and pretectal catecholaminergic neurons fail to develop, whereas both anatomical structures form at least in part. This suggests that Nodal signaling is required for catecholaminergic neuron specification. In summary, our results do not support the previously suggested dominant roles for sonic hedgehog and Fgf8 in specification of the first catecholaminergic neurons, but instead indicate a novel role for Nodal signaling in this process.