bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restricted Expression of the Actin-Regulatory Protein, Tropomyosin, Defines Distinct Boundaries, Evaginating Neuroepithelium, and Choroid Plexus Forerunners during Early CNS Development
Authors: Nicholson-Flynn Kelley , Hitchcock-DeGregori Sarah E. , Levitt Pat 
Published: April 2018

In the hindbrain, rhombomeres represent morphological units that develop characteristic, segment-specific structures. Similar segments, known as prosomeres, have been proposed to exist in the forebrain. The neuroepithelial cells of the sharp boundary regions that form the borders between many segments often exhibit distinct shapes, reflecting unique cytoskeletal organization. The present investigation examined the expression of one family of actin-binding, regulatory proteins, the tropomyosins (TM), in boundaries. We found that high molecular weight TMs selectively concentrate in boundary cells and other neuroepithelial zones that exhibit unique cell shapes and movements. Specific TM expression is found at hindbrain boundaries as early as embryonic day 10 in the rat, whereas rhombomeres themselves were TM-negative. Highly restricted TM localization also defined some prosomere boundaries in the early forebrain, particularly those exhibiting unique cell shapes. Furthermore, several regions of the neuroepithelium that evaginate are TM-immunoreactive, including tuberal and preoptic neuroepithelium. Most striking, a subpopulation of neuroepithelial cells in the medial telencephalic wall expresses TM, apparently marking the neuroepithelial region that gives rise to the choroid plexus at least 2 d before its formation. This suggests that the medial cerebral wall is not entirely dedicated to generating cells that comprise allocortex. TM expression in the choroid plexus is maintained through initial evagination and appearance in all ventricles. The spatially restricted expression of TMs implicates that this actin-binding protein is involved in the dynamic regulation of cell shape or motility associated with boundary formation and morphogenesis of the neuroepithelium during critical stages of brain development.
Hierarchical Organization of Auditory Temporal Context Sensitivity
Authors: Lewicki Michael S. , Arthur Benjamin J. 
Published: April 2018

Some of the most complex auditory neurons known are contained in the songbird forebrain nucleus HVc. These neurons are highly sensitive to auditory temporal context: they respond strongly to the bird’s own song, but respond weakly or not at all when the sequence of the song syllables is altered. It is not known whether this property arisesde novoin HVc or whether it is relayed from the properties of neurons in afferent nuclei. To address this issue, we recorded from neurons in both HVc and its afferent nuclei, collectively called field L. Experimental tests were designed to determine the degree of auditory context sensitivity in field L and HVc. Tests were also performed to compare the responses to individual syllables and syllable combinations to see whether these responses could account for the response seen to the entire song.Our results show a substantial increase in the auditory temporal context sensitivity between field L and HVc. Most field L neurons respond equally well both to normal song and to temporally manipulated versions of the same song. A few field L neurons show sensitivity to local temporal structure, such as the sequence of syllable pairs. In contrast, HVc neurons are highly dependent on the song’s local and global temporal structure. This shows that HVc neurons can integrate auditory context over periods much longer than neurons in field L and suggests that additional mechanisms are required to explain the marked sensitivity of HVc neurons to the temporal structure of the bird’s own song.
Enhancement of Behavioral and Electroencephalographic Indices of Waking following Stimulation of Noradrenergic β-Receptors within the Medial Septal Region of the Basal Forebrain
Authors: Berridge Craig W. , Foote Stephen L. 
Published: April 2018

Previous studies in halothane-anesthetized rat documented potent electroencephalographic (EEG) modulatory actions of the locus coeruleus (LC) noradrenergic system, with LC neuronal activity causally related to the maintenance of EEG activity patterns associated with enhanced arousal/alertness. Recent studies, also in halothane-anesthetized rat, demonstrated that the region of the basal forebrain encompassing the medial septum/vertical limb of the diagonal band of Broca (MS) is a site at which noradrenergic efferents act to influence EEG state via actions at β-receptors.These and other observations are consistent with the hypothesis that the LC noradrenergic system participates in the modulation of behavioral state. However, the degree to which this system modulates EEG state in the absence of anesthesia and to what extent such actions are accompanied by behavioral modulatory actions remain to be determined. The current studies examined whether small infusions of isoproterenol (ISO), a β-adrenergic agonist, into MS alter behavioral, EEG, and electromyographic (EMG) measures of sleep and waking in the resting, undisturbed rat.These infusions resulted in a significant increase in time spent awake, defined by both behavioral and EEG/EMG measures, and in the nearly complete suppression of REM sleep. EEG/EMG responses either coincided with or preceded behavioral responses by 10–320 sec. The pattern of behavioral responses observed following MS–ISO infusions was qualitatively similar to that associated with normal waking. Infusions of vehicle into MS or ISO into sites adjacent to MS did not elicit consistent alterations in behavioral state. These results suggest that the LC noradrenergic system exerts potent behavioral and EEG-activating effects via actions of norepinephrine at β-receptors located within MS.
Modulation of Forebrain Electroencephalographic Activity in Halothane-Anesthetized Rat via Actions of Noradrenergic β-Receptors within the Medial Septal Region
Authors: Berridge Craig W. , Bolen Sarah J. , Manley Michael S. , Foote Stephen L. 
Published: April 2018

The locus coeruleus (LC)–noradrenergic system modulates forebrain electroencephalographic (EEG) activity in halothane-anesthetized rat. For example, unilateral enhancement of LC neuronal activity increases cortical EEG (ECoG) and hippocampal EEG (HEEG) indices of arousal bilaterally (Berridge and Foote, 1991). Conversely, bilateral suppression of LC discharge activity increases EEG measures of sedation (Berridge et al., 1993b). The EEG-activating effects of LC stimulation appear to involve noradrenergic β-receptors (Berridge and Foote, 1991).Two candidate sites at which LC efferents could influence ECoG and HEEG are the medial septum/vertical limb of the diagonal band of Broca (MS) and the substantia innominata/nucleus basalis of Meynert (SI). To determine whether norepinephrine mediates such actions within either of these regions, the EEG effects of small infusions of a β-agonist or antagonist into MS or SI were examined in halothane-anesthetized rat. Unilateral infusions (150 nl) of the β-agonist isoproterenol (ISO) (3.75 μg, 17 nmol) into MS, but not SI (150–450 nl), elicited robust bilateral activation of ECoG and HEEG. Infusions of glutamate (0.5 μg, 3.0 nmol) into either MS or SI elicited bilateral ECoG and HEEG activation. Neither vehicle infusions into MS nor infusions of ISO into regions adjacent to MS altered forebrain EEG activity. Bilateral, but not unilateral, MS infusions of the β-antagonist timolol (3.75 μg, 8.7 nmol) decreased EEG indices of arousal in the lightly anesthetized preparation. Power spectral analyses provided quantitative confirmation of these qualitative observations.These results indicate that under these experimental conditions, noradrenergic efferents, presumably arising from LC, modulate forebrain EEG state via actions at β-receptors located within MS. The results presented in the accompanying report extend these observations to the unanesthetized preparation and incorporate additional measures of behavioral state.
Local Opioid Withdrawal in Rat Single Periaqueductal Gray NeuronsIn Vitro
Authors: Chieng Billy , Christie MacDonald J. 
Published: April 2018

Opioid dependence in ventrolateral periaqueductal gray (PAG) neurons was studied by using intracellular recordings from brain slices. In slices from morphine-dependent rats maintained in morphine (5 μm)in vitro, action potential frequencies of opioid-sensitive neurons did not differ from untreated control neurons but were greater than in control neurons maintained in morphinein vitro, indicating development of tolerance. Naloxone (100 nmor 1 μm) depolarized 25 of 51 neurons from morphine-dependent rats maintained in morphinein vitro, 19 of which previously had been classified as opioid-sensitive. Action potential frequencies in the presence of naloxone were greater than in control neurons in the absence of opioids, as well as in control neurons in the presence of both morphine and naloxone, demonstrating opioid withdrawal. In slices from control animals, opioid-induced hyperpolarizations and naloxone-induced depolarizations (in the presence of morphine) reversed polarity near expectedEK(−111 ± 3 mV and −113 ± 3 mV, respectively). In contrast, the reversal potential of naloxone-induced depolarizations was more negative than expected in neurons from dependent animals (−143 ± 9 mV), indicating that the depolarization was not attributable simply to antagonism of a K-conductance increase. Naloxone-induced depolarizations were not inhibited by tetrodotoxin (1 μm), bicuculline (30 μm), 6-cyano-7-nitroquinoxaline-2,3-dione (10 μm), or prazosin (300 nm), suggesting no involvement of major synaptic neurotransmitters. Clonidine (1 μm) and baclofen (30 μm) overcame naloxone-induced depolarizations. These results demonstrate development of both tolerance and withdrawal in PAG neurons and suggest induction of a novel opioid-sensitive current that could be involved in withdrawal behavior.
Methylmalonyl-CoA Mutase Induction by Cerebral Ischemia and Neurotoxicity of the Mitochondrial Toxin Methylmalonic Acid
Authors: Narasimhan Purnima , Sklar Robert , Murrell Matthew , Swanson Raymond A. , Sharp Frank R. 
Published: April 2018

Differential screening of gerbil brain hippocampal cDNA libraries was used to search for genes expressed in ischemic, but not normal, brain. The methylmalonyl-CoA mutase (MCM) cDNA was highly expressed after ischemia and showed a 95% similarity to mouse and 91% similarity to the human MCM cDNAs. Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain. MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex 8 and 24 hr after ischemia. Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold. Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia.Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase (SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain. This neurotoxicity is similar to that of structurally related mitochondrial SDH inhibitors, malonate and 3-nitropropionic acid. Methylmalonic acid may contribute to neuronal injury in human conditions in which it accumulates, including MCM mutations and B12deficiency. This study shows that methylmalonyl-CoA mutase is induced by several stresses, including ischemia, and would serve to decrease the accumulation of an endogenous cellular mitochondrial inhibitor and neurotoxin, methylmalonic acid.
Enhanced Amphetamine Sensitivity and Increased Expression of Dopamine D2 Receptors in Postpubertal Rats after Neonatal Excitotoxic Lesions of the Medial Prefrontal Cortex
Authors: Flores Gonzalo , Wood Graham K. , Liang Jin-Jun , Quirion Remi , Srivastava Lalit K. 
Published: April 2018

Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dopamine (DA) neurotransmission are thought to be the key pathologies in schizophrenia. To understand the role of MPFC in the pre- and postpubertal development of the subcortical DA system, the effects of neonatal [postnatal day 7 (PD7)] MPFC excitotoxic lesions on locomotor behaviors and the expression of DA receptor subtypes and DA transporter were investigated in Sprague Dawley rats at PD35 and PD56, respectively. No significant differences in the novelty ord-amphetamine-induced locomotion were observed between sham-operated and ibotenic acid-lesioned rats at PD35. Postpubertally (at PD56), however, the locomotor activity of lesioned rats in the novel environment and afterd-amphetamine administration was enhanced significantly compared with controls. The expressions of DA D1, D2, D3, and D4 receptors and DA transporter were then estimated in MPFC-lesioned and sham-operated rats at PD39 and PD60. The levels of DA D2 receptors, measured using [3H]-YM-09151-2 binding, and its mRNA byin situhybridization, were observed to be significantly increased at PD60 in striatal and limbic areas of lesioned rats. Levels of other DA receptor subtypes were not significantly affected at any time points. Lesioned rats at PD39 show a small increase in DA transporter level in the shell of nucleus accumbens; however, this effect seems to wear off at PD60. The data suggest that neonatal MPFC lesions may alter the functional development and maturation of mesolimbic/nigrostriatal DA systems in that neonatally lesioned rats grow into a behavioral/neurochemical deficit.
Growth Cone Form Is Behavior-Specific and, Consequently, Position-Specific along the Retinal Axon Pathway
Authors: Mason Carol A. , Wang Li-Chong 
Published: April 2018

Video time-lapse microscopy has made it possible to document growth cone motility during axon navigation in the intact brain. This approach prompted us to reanalyze the hypothesis, originally derived from observations of fixed tissue, that growth cone form is position-specific. The behaviors of DiI-labeled retinal axon growth cones were tracked from retina through the optic tract in mouse brain at embryonic day (E) 15–17, and these behaviors were matched with different growth cone forms. Patterns of behavior were then analyzed in the different locales from the retina through the optic tract.Throughout the pathway, episodes of advance were punctuated by pauses in extension. Irrespective of locale, elongated streamlined growth cones mediated advance and complex forms developed during pauses. The rate of advance and the duration of pauses were surprisingly similar in different parts of the pathway. In contrast, the duration of periods of advance was more brief in the chiasm compared to those in the optic nerve and tract. Consequently, in the chiasm, growth cones spent relatively more time pausing and less time advancing than in the optic nerve or tract. Thus, because growth cone form is behavior-specific and certain behaviors predominate in particular loci, growth cone form appears to be position-specific in static preparations, due to the fraction of time spent in a given state in different locales.
The Role of Internal Models in Motion Planning and Control: Evidence from Grip Force Adjustments during Movements of Hand-Held Loads
Authors: Flanagan J. Randall , Wing Alan M. 
Published: April 2018

We investigated the issue of whether or not the CNS makes use of an internal model of the motor apparatus in planning and controlling arm movements. In particular, we tested the ability of subjects to predict different hand-held loads by examining grip force adjustments used to stabilize the load in the hand during arm movements.Subjects grasped a manipulandum using a precision grip with the tips of the thumb and index finger on either side. The grip force (normal to the contact surfaces) and the load force (tangential to the surfaces) were measured, along with the trajectory of the hand. The manipulandum was attached to two servo-controlled linear motors used to create inertial and viscous loads as well as a composite load, including inertial, viscous, and elastic components.The form of the hand trajectory was independent of load for some subjects but varied systematically across load conditions in others. Nevertheless, under all load conditions and in all subjects, grip force was modulated in parallel with, and thus anticipated, fluctuations in load force despite the marked variation in the form of the load function. This indicates that the CNS is able to predict the load force and the kinematics of hand movement on which the load depends. We suggest this prediction is based on an internal model of the motor apparatus and external load and is used to determine the grip forces required to stabilize the load.
Properties of GABAAReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons
Authors: Galarreta Mario , Hestrin Shaul 
Published: April 2018

Rapid applications of GABA (from 10 μmto 10 mm) to outside-out patches were used to study the role that the kinetic properties of GABAAreceptors play in determining the time course of IPSCs in neocortical pyramidal neurons. Currents induced by rapid applications of brief (1 msec) pulses of GABA (1 mm) showed a biexponential decay phase that seems to involve the entry of GABAAreceptors into desensitized states. This conclusion is based on the similar fast decay kinetics of the response to brief and prolonged pulses of GABA and on the correlation between the degree of paired-pulse depression and the decay rate of the currents induced by brief pulses.Under nonequilibrium conditions we found that the concentration–response curve of pyramidal GABAAreceptors has an EC50of 185 μm(GABA pulse of 1 msec). The decay time course of the patch currents in response to brief applications of GABA was insensitive to agonist concentrations at the range from 50 μmto 10 mm. Faster decay rates were observed only in response to pulses of 10 μmGABA. These data are compatible with the suggestion that briefer openings derive from a monoliganded state and that these are negligible when receptor activation is >2%. Assuming that GABA transients at neocortical synapses are fast, a several millimolar GABA concentration would be needed to saturate the postsynaptic GABAAreceptors.
Angiotensin II AT1AReceptor mRNA Expression Is Induced by Estrogen–Progesterone in Dopaminergic Neurons of the Female Rat Arcuate Nucleus
Authors: Jöhren Olaf , Sanvitto Gilberto L. , Egidy Giorgia , Saavedra Juan M. 
Published: April 2018

Brain angiotensin II (Ang II) inhibits pituitary prolactin release by an indirect mechanism requiring stimulation of dopamine formation and release. We report that [125I]Sar1–Ang II binding to AT1receptors and AT1Areceptor mRNA expression increase selectively in the dorsomedial arcuate nucleus of 17β-estradiol-primed ovariectomized rats after treatment with progesterone. In hormone-treated rats, arcuate nucleus AT1Areceptor mRNA expression is associated with tyrosine hydroxylase-positive neurons. No AT1Areceptor mRNA was detected in tyrosine hydroxylase-positive cells of the arcuate nucleus of intact male rats. Conversely, in the anterior pituitary, where local or circulating Ang II stimulates prolactin release, [125I]Sar1–Ang II binding to AT1receptors and AT1Breceptor mRNA expression are decreased in 17β-estradiol/progesterone-treated ovariectomized rats.Thus, AT1Areceptors in the dorsal arcuate nucleus and AT1Breceptors in the anterior pituitary are regulated inversely by estrogen/progesterone treatment, supporting the hypothesis of a dual role for brain and pituitary Ang II on prolactin release. The colocalization of AT1Areceptor mRNA and tyrosine hydroxylase in neurons of the arcuate nucleus furthermore indicates that within this area central Ang II acts directly on dopaminergic neurons. These results support the hypothesis that central Ang II inhibits pituitary prolactin release indirectly via modulation of dopaminergic activity in the arcuate nucleus.
Transition from Growth Cone to Functional Motor Nerve Terminal inDrosophilaEmbryos
Authors: Yoshihara Motojiro , Rheuben Mary B. , Kidokoro Yoshiaki 
Published: April 2018

As a motor axon grows from the CNS to its target muscle, the terminal has the form of a flattened growth cone with a planar central region, lamellipodia, and filopodia. A mature terminal usually has a stereotyped shape that may be elongated with varicosities, as in several invertebrate species, or have short branches with boutons, as in mammals. We examined inDrosophilathe developmental changes between growth cone and mature terminal using ultrastructural and immunocytochemical methods.The transition period, which occurs 2–3 hr after the first growth cone reaches its target muscle, is marked by the formation of “prevaricosities,” smoothly contoured enlargements of the axons at the point where the nerve trunk first contacts the muscle fiber (MF). There is a 15–30 min ventral-to-dorsal gradient in the formation of prevaricosities on the individual abdominal MFs. Multineuronal innervation of each MF has occurred by this time, and two or more different axons undergo prevaricosity formation while they are intimately intertwined at the nerve entry point (NEP). Presynaptic active zones, both nerve–nerve and nerve–muscle, occur within the prevaricosities along broad contact regions. Synaptotagmin immunoreactive clusters form concurrently.The first varicosities then develop as a result of constrictions of the larger prevaricosities rather than as enlargement of discrete portions of the filopodia or neurites. The prevaricosity stage therefore may include the key steps that lead to the differentiation of functional differences in terminal subtypes as well as those leading to the formation of a stable neuromuscular junction.
Mechanoelectrical Transduction and Adaptation in Hair Cells of the Mouse Utricle, a Low-Frequency Vestibular Organ
Authors: Holt Jeffrey R. , Corey David P. , Eatock Ruth Anne 
Published: April 2018

Hair cells of inner ear organs sensitive to frequencies above 10 Hz adapt to maintained hair bundle deflections at rates that reduce their responses to lower frequencies. Mammalian vestibular organs detect head movements at frequencies well below 10 Hz. We asked whether hair cells of the mouse utricle adapt, and if so, whether the adaptation was similar to that in higher frequency organs such as the frog saccule.Whole-cell transduction currents were recorded from hair cells in the epithelium of the mouse utricle. Hair bundles were deflected by a fluid jet or a stiff probe. The transduction currents evoked by step deflections adapted over 10–100 msec. The mean operating range was 1.5 μm (deflection of the tip of the bundle), approximately threefold larger than in frog saccule. Taller and more compact bundles of the mouse utricle account for this difference. As in frog saccular hair cells, adaptation shifted the current–deflection (I(X)) relation along the deflection axis. These adaptive shifts had time constants of 10–20 msec and reached 60–80% of stimulus amplitude. The adaptive shift and voltage-dependent bundle movement are consistent with the motor model of adaptation. When the fluid jet was used, adaptation also broadened theI(X) relation and reduced the maximum current.Adaptation attenuated the transduction currents evoked by sinusoidal bundle deflections below 5 Hz, within the frequency range of the utricle, but because it was incomplete, substantial responses remained. Moreover, the adaptive shift mechanism preserves sensitivity even in the presence of large stimuli that would otherwise saturate transduction.