bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-recognition: a constraint on the formation of electrical coupling in neurons [published erratum appears in J Neurosci 1994 Jun;14(6):following table of contents]
Authors: Guthrie PB , Lee RE , Rehder V , Schmidt MF , Kater SB
Published: April 2018

Electrical coupling between specific neurons is important for proper function of many neuronal circuits. Identified cultured neurons from the snail Helisoma show a strong correlation between electrical coupling and presence of gap junction plaques in freeze-fracture replicas. Gap junction plaques, however, were never seen between overlapping neurites from a single neuron, even though those same neurites formed gap junctions with neurites from another essentially identical identified neuron. This observation suggests that a form of self-recognition inhibits reflexive gap junction formation between sibling neurites. When one or both of those growth cones had been physically isolated from the neuronal cell body, both electrical coupling and gap junction plaques, between growth cones from the same neuron, were observed to form rapidly (within 30 min). Thus, inhibition of electrical coupling between sibling neurites apparently depends on cytoplasmic continuity between neurites, and not the molecular composition of neurite membrane. The formation of gap junctions is not likely due to the isolation process; rather, the physical isolation appears to release an inhibition of reflexive gap junction formation. These data demonstrate the existence of a previously unknown constraint on the formation of electrical synapses.
Tactile discrimination capacity in relation to size and organization of somatic sensory cortex in primates: I. Old-World prosimian, Galago; II. New-World anthropoids, Saimiri and Cebus
Authors: Carlson M , Nystrom P
Published: April 2018

Living primates vary considerably in brain organization, in sensorimotor and cognitive abilities, and in natural behavioral repertoires. Comparative studies of primary (SI) and secondary (SII) somatic sensory cortex of primates reveal major differences in the size and in the complexity of topographic projection patterns. The separate projections of the glabrous hand to SI cytoarchitectonic areas 3b and 1 described in the Old World (OW) anthropoid Macaca and in New World (NW) anthropoids Cebus, Saimiri, and Aotus are lacking in NW Saguinus and in the prosimian Galago. The relationship between the size and complexity of SI organization and tactile abilities is explored in this study of four species of primates--Galago, Macaca, Cebus, and Saimiri. These species were trained to discriminate between pairs of objects differing either in cross-sectional diameter (size) or surface roughness (texture). The course of acquisition of such tactile discrimination in normal Macaca and the nature of deficits following SI or SII removals are known. Selective lesions of either cytoarchitectonic area 1 or 2 in Macaca affect only texture or size discriminations, respectively. Removal of area 3b in SI, or of SII, in Macaca affects both size and texture capacities. The single projection of the glabrous hand to area 3b-1 of Galago led to our expectation that the capacity of Galago to discriminate textures would be more similar to an area 1-lesioned than to a normal Macaca. The substantial and persistent differences between Macaca and Galago on texture, but not size, tasks lend support to the view that the evolution of a second projection of the glabrous hand to area 1 in Macaca contributes to increased texture discrimination capacity. The similarity in multiple projection patterns of the glabrous hand to areas 3b and 1 in Macaca, Saimiri, and Cebus led us to expect greater correspondence in texture discrimination capacity between these three anthropoids than to Galago. Contrary to expectations, Saimiri and Cebus showed a tactile capacity more similar to Galago than to Macaca. Furthermore, the texture discrimination capacity of Cebus actually improved substantially after removal of area 1. This provides further evidence, together with the single SI hand area in NW Saguinus and Galago, that the separate cutaneous projections to area 1 in OW and NW primates are not homologous but evolved independently and possibly serve different tactile functions.
Synaptic facilitation at connections of Hermissenda type B photoreceptors
Authors: Schuman EM , Clark GA
Published: April 2018

The enhancement of excitability in type B photoreceptors is an important neural mechanism underlying classically conditioned suppression of phototaxis in the marine mollusk Hermissenda crassicornis. However, the possibility that type B photoreceptors also exhibit synaptic plasticity has not previously been explored. We now report that connections of type B photoreceptors onto type A photoreceptors exhibit synaptic facilitation, and that this facilitation involves the same first messenger (5-HT) and second messenger (protein kinase C) previously implicated in the learning- produced excitability changes. In brief, we found that application of 5- HT dramatically facilitates synaptic potentials evoked by type B cells in type A cell cells, and that this facilitation is blocked by preincubation with staurosporine, a protein kinase inhibitor. Furthermore, activation of protein kinase C also induces synaptic facilitation, whereas activation of the cAMP-dependent protein kinase has no effect. Changes in synaptic strength produced by these manipulations are paralleled by changes in type B cell input resistance (a simple index of cellular excitability), whereas type A cell input resistance is unaffected. These findings indicate a previously unrecognized form of neuronal plasticity in Hermissenda that may contribute importantly to the learned changes in behavior, and thereby highlight general principles of learning-related neuronal plasticity shared by different preparations and species.
Synaptic inhibition influences the temporal coding properties of medial superior olivary neurons: an in vitro study
Authors: Grothe B , Sanes DH
Published: April 2018

The medial superior olive (MSO) functions as a coincidence detector for interaural time and phase differences by integrating excitatory synaptic inputs. Recent studies demonstrating glycinergic projections to MSO neurons suggest that coincidence detection results from the temporal integration of both EPSPs and IPSPs. We examined the impact of synaptic inhibition on the temporal coding properties of gerbil MSO neurons in vitro with intracellular recordings and electrical stimulation. For low-level bilateral electric stimulation, the EPSPs summated to produce an action potential in 73% of MSO neurons if they occurred within 50–500 microseconds of one another. Synaptic inhibition became more prominent at higher stimulus amplitudes in 73% of MSO neurons, and could block an evoked action potential if the stimuli to each pathway were delivered within 250 microseconds of one another. The glycine receptor antagonist strychnine influenced the response to simulated interaural time differences. In the presence of strychnine, interstimulus delays that originally resulted in full action potential suppression were sufficient to evoke an action potential. For trains of stimuli, as stimulus intensity increased (spatial summation), or as stimulus repetition rate increased to 100–500 Hz (temporal summation), there was a decrease in the number of stimulus pulses that evoked an action potential. In the presence of strychnine, MSO neurons generated a greater percentage of action potentials to the stimulus trains. When stimulus trains were delivered bilaterally, MSO neurons fired a greater number of action potentials at specific interstimulus time differences, and were selectively inhibited at other time differences.(ABSTRACT TRUNCATED AT 250 WORDS)
Alterations of the cortical representation of the rat ventrum induced by nursing behavior
Authors: Xerri C , Stern JM , Merzenich MM
Published: April 2018

The representation of the surfaces of the trunk was mapped in detail in a series of anesthetized adult female rats to assess cortical representational changes that might be induced in the SI cortical field by a major natural source of a differentially heavy schedule of tactile inputs: the stimulation of the rat ventrum in nursing behavior. Controls included virgin rats and postpartum age-matched rats whose litters were removed on the day of birth. The SI representation of the ventral trunk skin of lactating rats was about 1.6 x larger than in matched postpartum nonlactating or virgin controls. The greatest representational change--about twofold--was for the nipple-bearing skin between the forelimbs and hindlimbs. Indeed, changes in SI representational territory for the middle third of the ventrum, a skin zone without nipples, were not significant. As a rule, the representation of the ventrum skin in lactating rats was at least as topographically ordered as was that reconstructed for nonlactating postpartum and virgin controls. Receptive fields (RFs) representing the ventrum skin in lactating females were about one-third the sizes of those recorded in matched nonlactating or virgin controls. RF size differences were again greater for the representation of the nipple- bearing skin in the anterior and posterior thirds of the ventrum than for the central third. Changes in RF sizes were roughly inversely related to changes in the cortical magnification of representation of the ventrum on the proportion of about 3:2. Interestingly, the glabrous nipple and areolar skin were only weakly represented--or not demonstrably represented--in the SI map of either lactating or control rats. These results indicate that there is a largely unstudied cortical neurology of nursing behavior. Major CNS changes are induced by this dramatic, episodic change in behaviorally important tactile inputs. In turn, input-induced changes presumably contribute to this emergent, rapidly evolving behavior.
Differential ability of human cutaneous nociceptors to signal mechanical pain and to produce vasodilatation
Authors: Koltzenburg M , Handwerker HO
Published: April 2018

We investigated the ability of human nociceptive primary afferent neurons to encode mechanical pain and to produce vasodilatation. Pain was induced by shooting a light metal cylinder (0.3 g) at different velocities (6–18 m/sec) perpendicularly against the hairy skin of the hand. When single impact stimuli were applied, monotonically increasing stimulus-response functions were obtained in 10 psychophysical experiments using magnitude estimation techniques. In 35 microneurographic experiments nine unmyelinated afferents were recorded from the superficial radial nerve. All units responded readily to impact stimulation even at stimulus intensities that were not rated as painful. However, there was a close linear correlation between the number of action potentials evoked from the nociceptors and the psychophysical magnitude estimates of the perceived sensation or the stimulus intensity. This was also reflected by a corresponding increase of neurogenic vasodilatation. While two thin myelinated afferents displayed qualitatively similar responses 12 low-threshold mechanosensitive afferents (4 rapidly adapting, 5 slowly adapting type 1, 3 slowly adapting type II) failed to encode the intensity of the applied impact force and often became desensitized. This indicates that the total number of action potentials is the determinant of the magnitude of mechanical pain and the associated vasodilatation following single brief stimuli. By contrast, the close correlation between nociceptor activity and sensation changed when trains of mechanical impact stimuli (five stimuli of constant intensity, intratrain frequency of 1/32 to 2 Hz) were applied. Magnitude estimates of pain intensity were frequency dependent and stimuli with short interstimulus intervals were perceived as more painful than those delivered with long intervals. However, the total number of action potentials evoked from C-fibers was higher at longer interstimulus intervals than shorter intervals, thus yielding a negative correlation between the magnitude estimates of the perceived painful sensation and the number of action potentials elicited from nociceptive afferents. This suggests that temporal summation of the nociceptive discharge at central neurons becomes increasingly more important for the sensory discriminative experience of pain evoked by repetitive stimulation. We conclude that human nociceptive C-fibers signal brief noxious mechanical stimuli by the total number of action potentials evoked during a short period of time. However, with repetitive stimulation the total number of action potentials evoked from nociceptors is less important for evoking pain and temporal summation of the nociceptive primary afferent discharge becomes the crucial factor for signaling the magnitude of sensation.
Effects of intrahypothalamic administration of antisense DNA for progesterone receptor mRNA on reproductive behavior and progesterone receptor immunoreactivity in female rat
Authors: Ogawa S , Olazabal UE , Parhar IS , Pfaff DW
Published: April 2018

Since reproductive behaviors of female rats can be correlated with estrogen-induced increases in progestin binding by hypothalamic neurons, we hypothesized that specific progesterone receptor (PR) antisense DNA sequences might decrease these behaviors. Antisense oligonucleotides (15 bases), spanning the translation start site of rabbit PR mRNA, were microinjected directly among ventromedial hypothalamic neurons, and their behavioral effects were compared to control oligonucleotides composed of the same nucleotide bases in scrambled order. When applied 12 but not 24 hr after estradiol, the PR antisense treatment significantly reduced iordosis behavior, measured either as a reflex or in a mating behavior test. Notably, proceptive behaviors, which are strongly progesterone dependent, were greatly reduced in their occurrence (80% decrease). To see if PR protein was also reduced, antisense DNA was administered near the ventromedial hypothalamus on one side of the brain, while the other side received the scrambled control sequence or vehicle. The total number of PR- immunoreactive cells on the antisense side was significantly lower in the ventromedial nucleus, but not in control measurements from the medial preoptic area. Interrupting gene expression for PR, a transcription factor, in hypothalamic neurons, can have behavioral and immunocytochemical effects.
Learning and memory in the honeybee
Authors: Hammer M , Menzel R
Published: April 2018

Insects are favorable subjects for neuroethological studies. Their nervous systems are relatively small and contain many individually identifiable cells. The CNS is highly compartmentalized with clear separations between multisensory higher order neuropiles in the brain and neuropiles serving sensory-motor routines in the ventral cord (Huber, 1974). The rich behavior of insects includes orientation in space and time, visual, chemical, and mechanical communication, and complex motor routines for flying, walking, swimming, nest building, defense, and attack. Learning and memory, though, are not usually considered to be a strong point of insects. Rather, insect behavior is often regarded as highly stereotyped and under tight control of genetically programmed neural circuits. This view, however, does not do justice to the insect order of Hymenoptera (bees, wasps, ants). Most Hymenopteran species care for their brood either as individual females or as a social group of females. Consequently, they regularly return to their nest site to feed, protect, and nurse the larvae, store food, and hide from adverse environmental conditions. Since they search for food (prey; nectar and pollen on flowers) at unpredictable sites, they have to learn the celestial and terrestrial cues that guide their foraging trips over long distances and allow them to find their nest sites (central place foraging; von Frisch, 1967; Seeley, 1985). They learn to relate the sun's position and sky pattern of polarized light to the time of the day (Lindauer, 1959), and landmarks are learned in relationship to the nest site within the framework of the time- compensated sun compass. The honeybee communicates direction and distance of a feeding place to hive mates by performing a ritualized body movement, the waggle dance (von Frisch, 1967). Associative learning is an essential component of the bee's central place foraging behavior and dance communication. Hive mates attending a dance performance learn the odor emanating from the dancing bee and seek it at the indicated food site. The odor, color, and shape of flowers are learned when the bee experiences these stimuli shortly before it finds food (nectar, pollen). This appetitive learning in bees has many characteristics of associative learning well known from mammalian learning studies (Menzel, 1985, 1990; Bitterman, 1988). It follows the rules of classical and operant conditioning, respectively, so that stimuli or behavioral acts are associated with evaluating stimuli. Since associative learning, especially of the classical type, is well described at the phenomenological and operational level (Rescorla, 1988), it provides a favorable approach in the search for the neural substrate underlying learning and memory.(ABSTRACT TRUNCATED AT 400 WORDS)
Excitatory synaptic transmission in neostriatal neurons: regulation by cyclic AMP-dependent mechanisms
Authors: Colwell CS , Levine MS
Published: April 2018

The purpose of the present study was to examine whether cAMP-dependent mechanisms regulated excitatory synaptic transmission in the neostriatum. A brain slice preparation was utilized for intracellular recordings of the excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation. Bath application of forskolin, an activator of adenylate cyclase, enhanced the EPSP amplitude and duration. This potentiation was dose dependent and did not occur with the inactive analog 1,9-dideoxyforskolin. Forskolin potentiation was unaltered by treatment with the GABAA receptor antagonist bicuculline. Furthermore, two inhibitors of cAMP-dependent protein kinase (PKA), Rp-cAMPS and IP20-amide, attenuated forskolin's enhancement of the EPSP. In addition, the PKA activator Sp-cAMPS enhanced excitatory synaptic transmission. Interestingly, treatment with PKA inhibitors alone depressed while the phosphatase inhibitor okadaic acid enhanced the synaptic response. These results suggest a role for tonic kinase and phosphatase activity in regulating excitatory synaptic transmission in the neostriatum. Finally, forskolin was found to enhance the responses of neostriatal neurons to glutamate receptor agonists. This potentiation, which occurred in the presence of tetrodotoxin, provides at leas part of the explanation for the cAMP/PKA-dependent regulation of the EPSP. Overall, these results suggest a role for the adenylate cyclase cascade in the regulation of excitatory synaptic transmission in the neostriatum.
Genetic analysis of Drosophila neurons: Shal, Shaw, and Shab encode most embryonic potassium currents
Authors: Tsunoda S , Salkoff L
Published: April 2018

In this study, we perform the first genetic analysis of K+ currents in Drosophila embryonic neurons revealing the identity of the currents present. Unlike muscles, where the presence of Shaker is obvious, Shaker currents are not detectable in these neurons. In contrast, we show that Shal is as important in these neuronal cell bodies as Shaker is in muscles. Only three single-channel currents were found, all of which are genetically separable. Shal encodes a 4 pS transient channel. Whole-cell Shal currents have a wide variety of inactivation rates which, in contrast to a mechanism such as heteromultimer formation, is due to single Shal channels assuming different gating modes. Shaw encodes a 42 pS noninactivating channel distinctive for its extremely low voltage sensitivity; Shaw channels have a total equivalent gating charge of 0.90 e- charges, in sharp contrast to 7 e- reported for Shaker channels. An 11 pS slowly inactivating channel also present in these neurons may be encoded by the Shab gene. Thus, of four voltage- dependent K+ channel genes now cloned in Drosophila, all except Shaker appear to be expressed in the cell bodies of these neurons. It is only in Drosophila that a study such as this one can be done. Because Drosophila contains only a single member of each of the four subfamilies of K+ channel genes (unlike mammals), we can eliminate an entire subfamily with a mutation to a single gene. Here, we have examined the effect of eliminating each of three subfamilies. Such a task is presently impossible to accomplish in any mammalian system.
Monoamines and nitric oxide are employed by afferents engaged in midline thalamic regulation
Authors: Otake K , Ruggiero DA
Published: April 2018

The neurochemical identities of afferents to the midline thalamus were investigated in chloral hydrate-anesthetized adult Sprague-Dawley rats. The retrograde tracers, FluoroGold or cholera toxin B subunit, were centered on the paraventricular thalamic nucleus (n.Pvt), a periventricular member of the diffuse thalamocortical projection system that is reciprocally linked with visceral areas of cerebral cortex and implicated in food intake and addictive behavior. Tissues were processed with antisera raised against 5-HT, the catecholamine- synthesizing enzymes, tyrosine hydroxylase or phenylethanolamine N- methyltransferase or the cholinergic anabolic enzyme, ChAT. Serotonergic afferents principally derive from dorsal and median constituents of the mesopontine raphe. Previously unrecognized sources of catecholaminergic afferents were detected. Adrenergic afferents were traced to neurons in the C1 and C3 areas of rostral medullary reticular formation and periventricular gray, respectively, and the C2 area corresponding to the dorsal general viscerosensory field of nucleus tractus solitarii. Noradrenergic afferents arise principally from neurons in the locus ceruleus and A5 area. Dopaminergic projections to the n.Pvt derive from the A14, A13 and A11 cell groups in diencephalon. Afferents presumed to generate nitric oxide (NO) as a diffusible membrane-permeant transcellular signal were detected by processing retrogradely labeled tissues histochemically for NADPH-diaphorase, a molecule associated with nitric oxide synthase. NO in the n.Pvt is generated predominantly by noncholinergic neurons in the lateral hypothalamic area and mesopontine tegmentum. In striking contrast, extensive interactions were predicted between NO and ACh in the central medial and other loci in the nondiscriminative thalamus. We conclude that the n.Pvt is a site of interaction of NO and monoaminergic afferents derived from nuclei implicated in sensory gating, regulation of electrocortical neural activity and behavior. Taken collectively, our data predict that the labile transcellular messenger NO may enable structurally differentiated subnuclei of the diffuse thalamocortical projection system to act in concert as a functionally unified unit.
Cerebellar toxicity of phencyclidine
Authors: Nakki R , Koistinaho J , Sharp FR , Sagar SM
Published: April 2018

Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antagonists are toxic to neurons in the posterior cingulate and retrosplenial cortex. To determine if additional neurons are damaged, the distribution of microglial activation and 70 kDa heat shock protein (HSP70) induction was studied following the administration of PCP and MK801 to rats. PCP (10–50 mg/kg) induced microglial activation and neuronal HSP70 mRNA and protein expression in the posterior cingulate and retrosplenial cortex. In addition, coronal sections of the cerebellar vermis of PCP (50 mg/kg) treated rats contained vertical stripes of activated microglial in the molecular layer. In the sagittal plane, the microglial activation occurred in irregularly shaped patches, suggesting damage to Purkinje cells. In accord with this finding, PCP induced HSP70 protein and mRNA expression in Purkinje cells. Although there were relatively few foci of microglial activation and cells with HSP70 protein induction, HSP70 mRNA was detected in many Purkinje cells located throughout the cerebellar hemispheres as well as the vermis. MK801, at doses of 5–10 mg/kg, induced microglial activation and neuronal HSP70 mRNA and protein expression in the cingulate and retrosplenial cortex but not in the cerebellum. At the dose of 1 mg/kg MK801 induced HSP70 but did not consistently activate microglia. These data suggest that microglia are activated by MK801 doses that kill or severely damage neurons, whereas HSP70 is induced in “stressed” neurons at MK801 doses well below those that produce severe neurotoxicity. These observations suggest that PCP, but not MK801, is toxic to Purkinje cells and raise the question of whether NMDA antagonists or sigma ligands other than PCP are toxic to the cerebellum. Moreover, this study illustrates the usefulness of microglial activation and HSP70 induction as markers of neurotoxicity.
Functional interaction of melatonin receptors and D1 dopamine receptors in cultured chick retinal neurons
Authors: Iuvone PM , Gan J
Published: April 2018

The possible interaction of melatonin receptors and D1 dopamine receptors was investigated in neural cells prepared from embryonic day 8 chick retinas and cultured for 6 d. Dopamine stimulated cAMP accumulation in cultured retinal cells. This effect of dopamine was antagonized by addition of dopamine receptor antagonists (haloperidol and SCH23390) or melatonin receptor agonists (melatonin, 2- iodomelatonin, and 6-chloromelatonin). The inhibition of dopamine- stimulated cAMP accumulation by melatonin was concentration dependent, with half-maximal inhibition at approximately 160 pM. Melatonin inhibited the effect of dopamine at all dopamine concentrations, suppressing the maximal response to the neurotransmitter by approximately 70%. Melatonin also inhibited the stimulation of cAMP accumulation by SKF 82958, a selective D1 dopamine receptor agonist. Pretreatment of cultures with pertussis toxin had no significant effect on dopamine-stimulated cAMP accumulation, but inhibited the response to melatonin. In contrast to its effect on cAMP accumulation, melatonin had no effect on dopamine-stimulated inositol phosphate accumulation. These results suggest that melatonin receptors are coupled to dopamine receptor-regulated adenylate cyclase via an inhibitory G protein, and demonstrate another mechanism, in addition to inhibition of dopamine release, through which melatonin can modulate dopaminergic neurotransmission.
Noradrenergic neurons in the locus coeruleus of birds express TrkA, transport NGF, and respond to NGF
Authors: von Bartheld CS , Schober A , Kinoshita Y , Williams R , Ebendal T , Bothwell M
Published: April 2018

The chicken locus coeruleus contains a population of noradrenergic neurons which express the neurotrophin receptor p75 (von Bartheld and Bothwell, 1992). To determine which neurotrophin may regulate the development of noradrenergic neurons in the chicken locus coeruleus, expression of trk receptors, retrograde transport of neurotrophins, and responses to NGF were examined. P75-expressing noradrenergic neurons were found to project to the basal forebrain. They transport radio- iodinated NGF after injections into this target. The retrograde transport of NGF is specific to the noradrenergic neuronal population as evidenced by double labeling with antibodies against dopamine-beta- hydroxylase. The same neuronal population expresses trkA receptor mRNA. The size of noradrenergic neurons in the locus coeruleus proper, but not in the nucleus subcoeruleus, is significantly increased after injections of NGF into the telencephalon, consistent with the hypothesis that target-derived NGF provides trophic support. Noradrenergic coeruleus neurons are rescued from toxic effects of 6- hydroxydopamine injected into the telencephalon when NGF is injected into the midbrain. NGF has no rescue effect when it is coinjected with 6-hydroxy-dopamine into the telencephalon. In explant or dissociated cultures, noradrenergic coeruleus neurons do not respond to elevated levels of NGF with increased neurite outgrowth. Taken together, these results suggest that NGF plays a role in the development and maintenance of noradrenergic coeruleus neurons in the chick brain. The data also support our previous conclusion that major species differences exist between birds (chicken) and mammals with regard to trophic regulation of presumptive homologous neuronal populations.
High levels of synthesis and local effects of nerve growth factor in the septal region of the adult rat brain
Authors: Saporito MS , Carswell S
Published: April 2018

NGF found in the basal forebrain is believed to be localized to NGF- dependent cholinergic neurons and derived via retrograde axonal transport from NGF-synthesizing target hippocampal and cortical neurons. The basis for this concept of target-derived NGF is the detection of only limited amounts of NGF mRNA in the basal forebrain, despite relatively high NGF levels there. Our work, using a more sensitive and quantitative RNase protection method for detecting relative NGF mRNA levels, suggested, instead, relatively high levels of NGF mRNA synthesis in the septal region of the basal forebrain (BF-S), a region which contained primarily cells that project to the hippocampus. Similar results were obtained in analyses of a larger portion of the basal forebrain, designated “BF,” that encompassed cholinergic neurons that project to both the hippocampus and the cortex. The level of NGF mRNA measured in both BF-S and BF was equivalent to approximately 50% of the amount observed in the hippocampus. Furthermore, relative NGF mRNA levels detected in the BF- S, cortex, and hippocampus were shown to be proportional to NGF protein levels quantitated in each region. The detection of relatively high amounts of NGF synthesis in the BF-S was supported in studies demonstrating rapid NGF receptor (Trk) activation in the basal forebrain by exogenous NGF and in experiments showing that NGF mRNA was inducible in the BF-S by 1,25 dihydroxyvitamin D3. The extent of NGF mRNA induction was similar (approximately twofold) in the BF-S, hippocampus, and cortex, suggesting similar regulatory mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Visual short-term memory of stimulus velocity in patients with unilateral posterior brain damage
Authors: Greenlee MW , Lang HJ , Mergner T , Seeger W
Published: April 2018

Neurophysiological studies indicate the existence of an area in the extrastriate monkey cortex specialized for the processing of stimulus motion. The present investigation was conducted to determine whether a homologous area exits in the human cortex that underlies the processing and short-term storage of velocity information. Contrast detection and velocity discrimination thresholds were measured in a group of 23 patients with unilateral focal damage to either the lateral occipital, temporal, or posterior parietal cortex. Their results were compared to those of 23 age-matched control subjects. Detection and discrimination thresholds were determined for spatially truncated sinewave gratings presented 4 degrees eccentric of fixation randomly in either the left and right visual fields. Contrast detection thresholds were measured in a spatial two-alternative forced-choice paradigm for three different drift rates (1, 2, and 4 Hz) for leftward and rightward drift directions. Simultaneous velocity discrimination thresholds were determined for reference and test gratings presented 4 degrees left and right of fixation. Sequential velocity discrimination thresholds were measured using a delay, with a interstimulus interval (ISIs) of 1, 3, and 10 sec. In a subset of five patients with superior temporal lobe damage, spatial frequency discrimination thresholds for stationary gratings were also determined. The results indicate the following: (1) contrast detection thresholds for drifting gratings did not significantly differ between the patient and control groups; (2) velocity discrimination thresholds were significantly elevated in the patients; (3) velocity discrimination thresholds significantly increased with increasing ISI in the patients; (4) velocity discrimination thresholds were elevated most when the patients had a lesion in the superior temporal cortex; (5) in the subgroup of five patients with superior temporal lobe damage, spatial frequency discrimination thresholds were not significantly elevated. The results suggest that there is a visual area in the human posterior temporal cortex that is involved in the processing and short-term storage of the velocity of moving visual stimuli.
Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli
Authors: Campeau S , Davis M
Published: April 2018

The goal of this work was to test the involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning, using auditory and visual conditioned stimuli (CSs). The acoustic startle reflex in rats was used as the behavioral index of conditioning because startle is reliably enhanced in the presence of a conditioned stimulus (CS) previously paired with a footshock. Initially, differential conditioning procedures indicated reliable discrimination between a noise CS and a visual CS. Subsequently, the effects of amygdala lesions were evaluated when both modalities were paired with shocks in the same rats. Electrolytic or ibotenic acid lesions of the central nucleus of the amygdala blocked fear-potentiated startle to both auditory and visual CSs, consistent with the idea that the central nucleus serves as a response independent, final common relay for fear conditioning. Similarly, pre- or post-training electrolytic or NMDA- induced lesions of the basolateral complex of the amygdala, which damaged the lateral nucleus, and most of the basolateral nucleus, disrupted fear-potentiated startle to both CS modalities. This finding is consistent with the suggestion that, in fear conditioning, the basolateral complex of the amygdala serves as an obligatory relay of sensory information from subcortical and cortical sensory areas to the central nucleus of the amygdala.
The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C
Authors: Mestek A , Hurley JH , Bye LS , Campbell AD , Chen Y , Tian M , Liu J , Schulman H , Yu L
Published: April 2018

Opioids are some of the most efficacious analgesics used in humans. Prolonged administration of opioids, however, often causes the development of drug tolerance, thus limiting their effectiveness. To explore the molecular basis of those mechanisms that may contribute to opioid tolerance, we have isolated a cDNA for the human mu opioid receptor, the target of such opioid narcotics as morphine, codeine, methadone, and fentanyl. The receptor encoded by this cDNA is 400 amino acids long with 94% sequence similarity to the rat mu opioid receptor. Transient expression of this cDNA in COS-7 cells produced high-affinity binding sites to mu-selective agonists and antagonists. This receptor displays functional coupling to a recently cloned G-protein-activated K+ channel. When both proteins were expressed in Xenopus oocytes, functional desensitization developed upon repeated stimulation of the mu opioid receptor, as observed by a reduction in K+ current induced by the second mu receptor activation relative to that induced by the first. The extent of desensitization was potentiated by both the multifunctional calcium/calmodulin-dependent protein kinase and protein kinase C. These results demonstrate that kinase modulation is a molecular mechanism by which the desensitization of mu receptor signaling may be regulated at the cellular level, suggesting that this cellular mechanism may contribute to opioid tolerance in humans.
Amygdalo-entorhinal relations and their reflection in the hippocampal formation: generation of sharp sleep potentials
Authors: Pare D , Dong J , Gaudreau H
Published: April 2018

While the anatomical relations between the amygdala, parahippocampal cortices, and hippocampus have been studied extensively, little is known about how they interact. To address this issue, we studied the timing of entorhinal (ENT), subicular, and basolateral amygdaloid (BL) discharges with respect to previously unknown population events, hereafter termed sharp potentials (SPs), that appear in the ENT cortex of cats during EEG-synchronized states. SPs occurred in two forms. Simple SPs were monophasic potentials, negative in deep ENT layers and positive in layer I. Complex SPs appeared as simple SPs interrupted by a brief potential of opposite polarity. Simple SPs had no hippocampal correlate whereas complex SPs were followed by large potentials that could be recorded at several levels of the hippocampal loop under barbiturate anesthesia, but not beyond the dentate gyrus in natural sleep. In agreement with this, layer II ENT neurons and most subicular cells fired only in relation to complex SPs under anesthesia. Layer II ENT neurons fired in phase with SPs whereas subicular neurons fired 20– 40 msec later. In contrast, BL cells, layers IV-VI and layer III ENT neurons fired sequentially in relation to SPs with BL cells discharging as early as 40 msec before SPs. Finally, amygdala lesions abolished ENT SPs. These results suggest that the BL complex plays an essential role in the generation of population events that are transmitted to the ENT cortex. This is the first demonstration that spontaneous events occurring in the amygdala are reflected in the activity of related cortices. In turn, layer II ENT neurons gate the transfer of incoming inputs to the hippocampus. These findings shed light on the elaboration of normal and pathological activities in the amygdalo-hippocampal network.
Protein Kinase C Activation Regulates Human Serotonin Transporters in HEK-293 Cells via Altered Cell Surface Expression
Authors: Qian Yan , Galli Aurelio , Ramamoorthy Sammanda , Risso Stefania , DeFelice Louis J. , Blakely Randy D.
Published: April 2018

Antidepressant- and cocaine-sensitive serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) dictate clearance of extracellular 5-HT after release. To explore protein kinase C-mediated SERT regulation, we generated a stable human SERT (hSERT)-expressing cell line (293-hSERT) and evaluated modulation of 5-HT activity via studies of 5-HT flux, hSERT-mediated currents under voltage clamp, and surface distribution of SERT protein. 293-hSERT cells exhibit saturable, high-affinity, and antidepressant-sensitive 5-HT uptake as well as hSERT-dependent whole-cell currents. In these cells, the protein kinase C activator β-PMA caused a time-dependent reduction in 5-HT uptake capacity (Vmax) after acute application and a reduction in SERT-mediated currents. Effects of β-PMA were mimicked by the phorbol ester β-PDBu, were not observed with the inactive α-isomers, and could be blocked by treatment of cells with the protein kinase C inhibitor staurosporine. Biotinylation/immunoblot analyses showed that activity reductions are paralleled by a staurosporine-sensitive loss of surface SERT protein. These data indicate that altered surface abundance, rather than reduced catalytic transport efficiency, mediates acute PKC-dependent modulation of 5-HT uptake.
Single-Channel Properties of Recombinant AMPA Receptors Depend on RNA Editing, Splice Variation, and Subunit Composition
Authors: Swanson Geoffrey T. , Kamboj Sunjeev K. , Cull-Candy Stuart G.
Published: April 2018

Non-NMDA glutamate receptor subunits of the AMPA-preferring subfamily combine to form ion channels with heterogeneous functional properties. We have investigated the effects of RNA editing at the Q/R site, splice variation of the “flip/flop” cassette, and multimeric subunit assembly on the single-channel conductance and kinetic properties of the recombinant AMPA receptors formed from GluR2 and GluR4 expressed in HEK 293 cells. We found that AMPA receptor single-channel conductance was dependent on the Q/R site editing state of the subunits comprising the channel. Calcium-permeable (unedited) channels had resolvable single-channel events with main conductance states of 7–8 pS, whereas fully edited GluR2 channels had very low conductances of ∼300 fS (estimated from noise analysis). Additionally, the flip splice variant of GluR4 conferred agonist-dependent conductance properties reminiscent of those found for a subset of AMPA receptors in cultured cerebellar granule cells. These results provide a description of the single-channel properties of certain recombinant AMPA receptors and suggest that the single-channel conductance may be determined by the expression of edited GluR2 subunits in neurons.
The Role of Synaptic and Voltage-Gated Currents in the Control of Purkinje Cell Spiking: A Modeling Study
Authors: Jaeger Dieter , De Schutter Erik , Bower James M.
Published: April 2018

We have used a realistic computer model to examine interactions between synaptic and intrinsic voltage-gated currents during somatic spiking in cerebellar Purkinje cells. We have shown previously that this model generates realisticin vivopatterns of somatic spiking in the presence of continuous background excitatory and inhibitory input (De Schutter and Bower, 1994b). In the present study, we analyzed the flow of synaptic and intrinsic currents across the dendritic membrane and the interaction between the soma and dendrite underlying this spiking behavior. This analysis revealed that: (1) dendritic inward current flow was dominated by a noninactivating P-type calcium current, resulting in a continuous level of depolarization; (2) the mean level of this depolarization was controlled by the mean rate of excitatory and inhibitory synaptic input; (3) the synaptic control involved a voltage-clamping mechanism exerted by changes of synaptic driving force at different membrane potentials; (4) the resulting total current through excitatory and inhibitory synapses was near-zero, with a small outward bias opposing the P-type calcium current; (5) overall, the dendrite acted as a variable current sink with respect to the soma, slowing down intrinsic inward currents in the soma; (6) the somato-dendritic current showed important phasic changes during each spike cycle; and (7) the precise timing of somatic spikes was the result of complex interactions between somatic and dendritic currents that did not directly reflect the timing of synaptic input. These modeling results suggest that Purkinje cells act quite differently from simple summation devices, as has been assumed previously in most models of cerebellar function. Specific physiologically testable predictions are discussed.
Induction of Cell Proliferation by Fibroblast and Insulin-Like Growth Factors in Pure Rat Inner Ear Epithelial Cell Cultures
Authors: Zheng J. Lisa , Helbig Christian , Gao Wei-Qiang
Published: April 2018

Proliferation of supporting cells in the inner ear is the early major event occurring during hair cell regeneration after acoustic trauma or aminoglycoside treatment. In the present study, we examined the possible influence of 30 growth factors on the proliferation of pure rat utricular epithelial cells in culture. Utricular epithelial sheets were separated and partially dissociated from early postnatal rats via a combined enzymatic and mechanical method. The cultured utricular epithelial cells expressed exclusively epithelial cell antigens, but not fibroblast, glial, or neuronal antigens. With tritiated thymidine incorporation assays, we found that several fibroblast growth factor (FGF) family members, insulin-like growth factor-1 (IGF-1), IGF-2, transforming growth factor-α (TGF-α), and epidermal growth factor (EGF), stimulated proliferation of the utricular epithelial cells. In contrast, neurotrophins and other growth factors did not elicit any detectable mitogenic effects. Among all of the growth factors examined, FGF-2 was the most potent mitogen. When FGF-2 was added in combination with IGF-1 or TGF-α to the medium, combined effects were seen. These results were confirmed with BrdU immunocytochemistry. Thus, the present culture system provides a rapid and reliable assay system to screen novel growth factors involved in proliferation of mammalian inner ear supporting cells. Furthermore, immunostainings revealed that the cultured utricular epithelial cells expressed FGF and IGF-1 receptors, and utricular hair cells produced FGF-2in vivo. The addition of neutralizing antibodies against FGF-2 or IGF-1 to the cultures significantly inhibited the utricular epithelial cell proliferation. This work suggests that FGF-2 and IGF-1 may regulate the proliferation step during hair cell development and regeneration.
Registration of Neural Maps through Value-Dependent Learning: Modeling the Alignment of Auditory and Visual Maps in the Barn Owl’s Optic Tectum
Authors: Rucci Michele , Tononi Giulio , Edelman Gerald M.
Published: April 2018

In the optic tectum (OT) of the barn owl, visual and auditory maps of space are found in close alignment with each other. Experiments in which such alignment has been disrupted have shown a considerable degree of plasticity in the auditory map. The external nucleus of the inferior colliculus (ICx), an auditory center that projects massively to the tectum, is the main site of plasticity; however, it is unclear by what mechanisms the alignment between the auditory map in the ICx and the visual map in the tectum is established and maintained. In this paper, we propose that such map alignment occurs through a process of value-dependent learning. According to this paradigm, value systems, identifiable with neuromodulatory systems having diffuse projections, respond to innate or acquired salient cues and modulate changes in synaptic efficacy in many brain regions. To test the self-consistency of this proposal, we have developed a computer model of the principal neural structures involved in the process of auditory localization in the barn owl. This is complemented by simulations of aspects of the barn owl phenotype and of the experimental environment. In the model, a value system is activated whenever the owl carries out a foveation toward an auditory stimulus. A term representing the diffuse release of a neuromodulator interacts with local pre- and postsynaptic events to determine synaptic changes in the ICx. Through large-scale simulations, we have replicated a number of experimental observations on the development of spatial alignment between the auditory and visual maps during normal visual experience, after the retinal image is shifted through prismatic goggles, and after the reestablishment of normal visual input. The results suggest that value-dependent learning is sufficient to account for the registration of auditory and visual maps of space in the OT of the barn owl, and they lead to a number of experimental predictions.