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PubMed1996

CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef.

The human immunodeficiency virus type 1 (HIV-1) genes vpu, env, and nef have all been implicated in modulating the levels of cell surface CD4 on infected cells. To quantitatively assess the relative contribution of each gene product to the regulation of CD4 during HIV infection of Jurkat T cells and peripheral blood mononuclear cells, we have developed an infectious HIV reporter system which expresses different combinations of these genes. To distinguish infected cells in the early or late stages of infection from uninfected cells, these viruses were designed to express human placental alkaline phosphatase with the kinetics of either early or late viral genes. Flow cytometry to detect placental alkaline phosphatase and CD4 in infected cells showed that vpu, env, and nef are independently capable of down-modulation of CD4. As predicted by their respective expression patterns, nef down-modulated CD4 rapidly during the early phase of virus infection whereas vpu and env functioned late in the infection. In both Jurkat cells and peripheral blood mononuclear cells, a combination of the three genes was more efficient than any one or two genes, demonstrating that all three genes are required to achieve maximal CD4 down-modulation. In primary cells, down-modulation of CD4 was less efficient than in Jurkat cells and there was a stronger dependence on nef function for reducing cell surface CD4. HIV therefore has three genes that are able to independently down-modulate CD4; together, they can eliminate the bulk of cell surface CD4.

Alkaline Phosphatase↗
PubMed2000

Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3zeta and CD28, key signaling molecules for T-cell activation.

Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV-infected donors down-modulate CD3zeta, the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3zeta down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3zeta-down-modulated subset. HIV-specific CD8 T cells, identified by tetramer staining, are CD3zeta(-). CD8 T cells with down-modulated CD3zeta also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (HLA-DR(+) CD62L(-)). After T-cell activation, CD3zeta-down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor alpha-chain CD25 and produce gamma interferon but not IL-2. Therefore HIV-specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation. The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3zeta is not reexpressed even after IL-2 exposure.

CD28 Antigens↗
PubMed2005

A novel integrin alpha5beta1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells.

BACKGROUND: Connective tissue growth factor (CCN2) is upregulated in pancreatic fibrosis and desmoplastic pancreatic tumours. CCN2 interacts with integrin alpha5beta1 on pancreatic stellate cells (PSC) in which it stimulates fibrogenesis, adhesion, migration, and proliferation. AIM: To determine the structural domain(s) in CCN2 that interact with integrin alpha5beta1 to regulation PSC functions. METHODS: Primary activated rat PSC were tested for their adherence to isoforms of CCN2 comprising modules 1-4 (CCN2(1-4)), modules 3-4 (CCN2(3-4)), module 3 alone (CCN2(3)), or module 4 alone (CCN2(4)). Adhesion studies were performed in the presence of EDTA, divalent cations, anti-integrin alpha5beta1 antibodies, CCN2 synthetic peptides, or heparin, or after pretreatment of the cells with heparinase, chondroitinase, or sodium chlorate. CCN2 integrin alpha5beta1 binding was analysed in cell free systems. The ability of CCN2(1-4), CCN2(3-4), or CCN2(4) to stimulate PSC migration was evaluated in the presence of anti-integrin alpha5beta1 or heparin. RESULTS: PSC adhesion was stimulated by CCN2(1-4), CCN2(3-4), or CCN2(4) and supported by Mg2+ but not Ca2+. CCN2(4) supported PSC adhesion or migration were blocked by anti-integrin alpha5beta1 antibodies or by treatment of cells with heparinase or sodium chlorate. A direct interaction between CCN2(4) and integrin alpha5beta1 was demonstrated in cell free assays. The sequence GVCTDGR in module 4 mediated the binding between CCN2(4) and integrin alpha5beta1 as well as CCN2(4) mediated PSC adhesion and migration. CONCLUSIONS: A GVCTDGR sequence in module 4 of CCN2 is a novel integrin alpha5beta1 binding site that is essential for CCN2 stimulated functions in PSC and which represents a new therapeutic target in PSC mediated fibrogenesis.

Animals↗
PubMed1988

Modulation of ion channels in neurons and other cells.

The field of ion channel modulation has entered a stage of maturity. The development of powerful new molecular biological and biophysical approaches has provided important new insights into the structure and function of ion channels and has revealed them as dynamic entities whose activity can be regulated. The physiological consequences of such regulation are obvious for so-called excitable cells like nerve and muscle cells, but it is also evident that modulation occurs in many other cell types, where its effects on the lifestyle of the cell are less clear. Furthermore, the number of ion channels that have been shown to be subject to modulation continues to increase, and the end is not yet in sight. For example, exciting information is beginning to emerge about gating and conduction properties of the large class of channels coupled to excitatory amino acid receptors (Mayer 1987), but their modulation has not yet been studied in any detail. In any event, there no longer is any doubt that modulatability is an intrinsic property of many and perhaps all membrane ion channels. The mechanisms of channel modulation are also turning out to be more diverse than was first suspected. One possible explanation for this diversity is to provide a broad temporal spectrum for the regulation of channel activity. One temporal extreme may be a directly coupled system such as the nicotinic acetylcholine receptor/channel, where interactions between the several subunits of a single macromolecular complex determine rapid channel gating. The other extreme may be covalent modification (by protein phosphorylation or other covalent change), which results in a functional change that can long outlast the initial stimulus. G-protein modulation, which involves the (presumably) noncovalent interaction between distinct membrane proteins, may provide for intermediate duration changes in channel properties. Whether these mechanisms will be joined by others that provide for an even more subtle temporal discrimination is an exciting question for the future.

Animals↗
PubMed2007

Allosteric modulation of G protein-coupled receptors.

The past decade has witnessed a significant growth in the identification of allosteric modulators of G protein-coupled receptors (GPCRs), i.e., ligands that interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Because of their ability to modulate receptor conformations in the presence of orthosteric ligand, allosteric modulators can "fine-tune" classical pharmacological responses. This is advantageous in terms of a potential for engendering greater GPCR subtype-selectivity, but represents a significant challenge for detecting and validating allosteric behaviors. Although allosteric sites need not have evolved to accommodate endogenous ligands, there are a number of examples of where such modulators have been shown to contribute to physiological or pathophysiological processes. Studies are also beginning to unravel the structural basis of allosteric modulation of GPCRs. It remains to be determined whether such modulation represents interactions within monomers versus across dimers.

Allosteric Regulation↗
PubMed2003

Hypertension module: an interactive learning tool in physiology.

The aim of the present study was to evaluate the strong or weak aspects of an interactive study module introduced during the "Cardiovascular and Respiratory Systems Subject Committee" in the second year of the medical program. Five study groups consisting of 25 students attended two-hour module sessions for six weeks with the same tutor. According to the module assessment questionnaire, the majority of the students assessed the module as excellent or good. The students reported that they had gained not only in knowledge but also in skills development. The general opinion of the students was that both the organization and the implementation of the module met their expectations. Nearly one-half of the students reported that their expectations with regard to the educational environment and the participation of students were fully met. The major weakness in this new educational trial appears to be assessment of the module.

Education, Medical↗
PubMed2006

It's difficult to change the way we teach: lessons from the Integrative Themes in Physiology curriculum module project.

The Integrative Themes in Physiology (ITIP) project was a National Science Foundation-funded collaboration between the American Physiological Society (APS) and the Human Anatomy and Physiology Society (HAPS). The project goal was to create instructional resources that emphasized active learning in undergraduate anatomy and physiology classrooms. The resources (activity modules and professional development) addressed two factors thought to be limiting science education reform: instructors' knowledge of how to implement active learning instruction and time to design innovative curricula. Volunteer instructors with a strong interest in using active learning in their classrooms were recruited to use the ITIP modules and provide ease-of-use feedback and student assessment data. As the study unfolded, instructor attrition was higher than had been anticipated, with 17 of 36 instructors withdrawing. More surprisingly, instructors remaining with the project failed to use the modules and reported specific obstacles that precluded module use, including lack of support from academic leadership, unplanned class size increases and heavy teaching loads, a union strike, insufficient time to develop a mindset for change, inadequate technology/funding, an adverse human subjects ruling, incompatibility of modules with instructors' established content and expectations, and personal factors. Despite the lack of module use and obstacles, 8 of 19 site testers began independently to introduce new active learning instruction into their classrooms. In the larger picture, however, it is important to note that only 8 of the initial 36 volunteers (22%) actually ended up changing their instruction to include opportunities for student active learning. These findings underscore the difficulty of implementing instructional change in college classrooms.

Curriculum↗
PubMed2002

Modulation of BK(Ca) channel activity by fatty acids: structural requirements and mechanism of action.

To determine the mechanism of fatty acid modulation of rabbit pulmonary artery large-conductance Ca2+ -activated K+ (BK(Ca)) channel activity, we studied effects of fatty acids and other lipids on channel activity in excised patches with patch-clamp techniques. The structural features of the fatty acid required to increase BK(Ca) channel activity (or average number of open channels, NP(o)) were identified to be the negatively charged head group and a sufficiently long (C > 8) carbon chain. Positively charged lipids like sphingosine, which have a sufficiently long alkyl chain (C >or= 8), produced a decrease in NP(o). Neutral and short-chain lipids did not alter NP(o). Screening of membrane surface charge with high-ionic-strength bathing solutions (330 mM K+ or 130 mM K+, 300 mM Na+) did not alter the modulation of the BK(Ca) channel NP(o) by fatty acids and other charged lipids, indicating that channel modulation is unlikely to be due to an alteration of the membrane electric field or the attraction of local counterions to the channel. Fatty acids and other negatively charged lipids were able to modulate BK(Ca) channel activity in bathing solutions containing 0 mM Ca2+, 20 mM EGTA, suggesting that calcium is not required for this modulation. Together, these results indicate that modulation of BK(Ca) channels by fatty acids and other charged lipids most likely occurs by their direct interaction with the channel protein itself or with some other channel-associated component.

Amines↗
PubMed2005

Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation.

Cardiovascular autonomic modulation during 36 h of total sleep deprivation (SD) was assessed in 18 normal subjects (16 men, 2 women, 26.0 +/- 4.6 yr old). ECG and continuous blood pressure (BP) from radial artery tonometry were obtained at 2100 on the first study night (baseline) and every subsequent 12 h of SD. Each measurement period included resting supine, seated, and seated performing computerized tasks and measured vigilance and executive function. Subjects were not supine in the periods between measurements. Spectral analysis of heart rate variability (HRV) and BP variability (BPV) was computed for cardiac parasympathetic modulation [high-frequency power (HF)], sympathetic modulation [low-frequency power (LF)], sympathovagal balance (LF/HF power of R-R variability), and BPV sympathetic modulation (at LF). All spectral data were expressed in normalized units [(total power of the components/total power-very LF) x 100]. Spontaneous baroreflex sensitivity (BRS), based on systolic BP and pulse interval powers, was also measured. Supine and sitting, BPV LF was significantly increased from baseline at 12, 24, and 36 h of SD. Sitting, HRV LF was increased at 12 and 24 h of SD, HRV HF was decreased at 12 h SD, and HRV LF/HF power of R-R variability was increased at 12 h of SD. BRS was decreased at 24 h of SD supine and seated. During the simple reaction time task (vigilance testing), the significantly increased sympathetic and decreased parasympathetic cardiac modulation and BRS extended through 36 h of SD. In summary, acute SD was associated with increased sympathetic and decreased parasympathetic cardiovascular modulation and decreased BRS, most consistently in the seated position and during simple reaction-time testing.

Adolescent↗
PubMed2003

Cyclic h-reflex modulation in resting forearm related to contractions of foot movers, not to foot movement.

During rhythmic voluntary oscillations of the foot, the excitability of the H-reflex in the Flexor Carpi Radialis (FCR) muscle of the resting prone forearm increases during the foot plantar-flexion and decreases during dorsiflexion. It is known that, when the two extremities are moved together, isodirectional (in-phase) coupling is the preferred form of movement association. Thus the above pattern of the H-reflex excitability modulation may favor the preferred coupling between the two limbs. To gain some clues about its origin, FCR H-reflex excitability was tested before and after modifying the phase relations between the activation [electromyogram (EMG)] of foot movers and foot movement, either by loading of the foot or by changing the movement frequency. After foot loading, the movement cycle was consistently delayed with respect to the onset of the EMG in Soleus (Sol) or Tibialis Anterior (TA) muscles. Simultaneously, the FCR H-reflex modulation advanced by that same amount with respect to the foot movement, thus remaining phase-locked to the EMG onsets. Similarly, when movement frequency was varied step-wise between 1.0 and 2.0 Hz, the foot movement was progressively delayed with respect to both the EMG onset (Sol and TA) and the FCR H-reflex modulation, so that the phase relation between the motor command to the foot and the H-modulation in the forearm remained constant. These results suggest that modulation of H-reflex in the forearm is tied to leg muscle contraction, rather than to foot kinematics, and point to a central, rather than kinesthetic, origin for the modulation.

Biomechanical Phenomena↗
PubMed2003

ERK integrates PKA and PKC signaling in superficial dorsal horn neurons. I. Modulation of A-type K+ currents.

The transient outward potassium currents (also known as A-type currents or IA) are important determinants of neuronal excitability. In the brain, IA is modulated by protein kinase C (PKC), protein kinase A (PKA), and extracellular signal-related kinase (ERK), three kinases that have been shown to be critical modulators of nociception. We wanted to determine the effects of these kinases on IA in superficial dorsal horn neurons. Using whole cell recordings from cultured mouse spinal cord superficial dorsal horn neurons, we found that PKC and PKA both inhibit IA in these cells, and that PKC has a tonic inhibitory action on IA. Further, we provide evidence supporting the hypothesis that PKC and PKA do not modulate IA directly, but rather act as upstream activators of ERKs, which modulate IA. These results suggest that ERKs serve as signal integrators in modulation of IA in dorsal horn neurons and that modulation of A-type potassium currents may underlie aspects of central sensitization mediated by PKC, PKA, and ERKs.

Animals↗
PubMed2006

Responses of neurons in the ventral nucleus of the lateral lemniscus to sinusoidally amplitude modulated tones.

Fluctuations in the amplitude of a sound play an important role in our perception of pitch and acoustic space, but their neural analysis has not been fully elucidated. The ventral nucleus of the lateral lemniscus (VNLL) has been implicated in the processing of such temporal features of a sound. This study examines responses of neurons in the VNLL of unanesthetized rabbits to sinusoidally amplitude modulated tones, a type of stimulus that has often been used to investigate encoding of temporal information. Modulation transfer functions of responses were calculated in two ways: based on discharge rates (rMTFs) and on synchronization to the envelope (tMTFs). Among the variety of rMTFs, two types were readily identifiable: flat and band-pass. The responses of neurons exhibiting these types of rMTF differed in several ways. Neurons with flat rMTFs typically had moderate rates of spontaneous activity, sustained responses to short tone bursts, and low-pass or band-pass tMTFs. Neurons with band-pass rMTFs typically had low spontaneous activity, onset responses to short tone bursts, and flat tMTFs. The vast majority synchronized strongly to the modulation envelope. The best modulation frequencies of neurons with band-pass rMTFs extended from 14 to 283 Hz. The presence of neurons with band-pass rMTFs in the VNLL suggests that this nucleus plays a role in converting the temporal code for modulation frequency used in lower structures into a rate-based code for use higher in the auditory pathway. The substantial number of neurons with more complex modulation transfer functions indicates that the VNLL has other functions.

Acoustic Stimulation↗
PubMed2005

Temperature compensation of neuromuscular modulation in aplysia.

Physiological systems that must operate over a range of temperatures often incorporate temperature-compensatory mechanisms to maintain their output within a relatively narrow, functional range of values. We analyze here an example in the accessory radula closer (ARC) neuromuscular system, a representative part of the feeding neuromusculature of the sea slug Aplysia. The ARC muscle's two motor neurons, B15 and B16, release, in addition to ACh that contracts the muscle, modulatory peptide cotransmitters that, through a complex network of effects in the muscle, shape the ACh-induced contractions. It is believed that this modulation is critical in optimizing the performance of the muscle for successful, efficient feeding behavior. However, previous work has shown that the release of the modulatory peptides from the motor neurons decreases dramatically with increasing temperature. From 15 to 25 degrees C, for example, release decreases 20-fold. Yet Aplysia live and feed successfully not only at 15 degrees C, but at 25 degrees C and probably at higher temperatures. Here, working with reduced B15/B16-ARC preparations in vitro as well as a mathematical model of the system, we have found a resolution of this apparent paradox. Although modulator release decreases 20-fold when the temperature is raised from 15 to 25 degrees C, the observed modulation of contraction shape does not decrease at all. Two mechanisms are responsible. First, further downstream within the modulatory network, the modulatory effects themselves-experimentally dissected by exogenous modulator application-have temperature dependencies opposite to that of modulator release, increasing with temperature. Second, the saturating curvature of the dose-response relations within the network diminishes the downstream impact of the decrease of modulator release. Thus two quite distinct mechanisms, one depending on the characteristics of the individual components of the network and the other emerging from the network's structure, combine to compensate for temperature changes to maintain the output of this physiological system.

Animals↗
PubMed1990

Role of arachidonic acid in depolarization-induced modulation of ion currents in Aplysia giant neurons.

1. The effects of membrane depolarization on inward currents subsequently elicited by hyperpolarization were studied with the use of two-electrode, voltage-clamp techniques in the giant neurons LP1 and R2 of Aplysia. 2. Several successive sets of brief depolarizing pulses, or bursts, were used to depolarize the giant neurons. Two distinct inward currents elicited by hyperpolarization were found to be altered after these sets of depolarizing pulses. These currents were distinguished by their voltage dependence, reversal potential, and sensitivity to 1 mM BaCl2. One of the inward currents was increased after depolarization. It was outwardly rectifying, reversed at -50 mV, and not blocked by Ba2+, suggesting it was a chloride current (ICl). The other inward current, which was decreased after depolarization, was inwardly rectifying, reversed at -70 mV, and completely inhibited by Ba2+. These are characteristics of the inwardly rectifying potassium current (IR), a current previously described to be inhibited after depolarization in Aplysia neuron R 15. Depolarization typically increased the putative ICl and decreased IR for minutes, with the decrease in IR consistently outlasting the increase in an initial brief net increase in inward current followed by a long-lasting decrease. 3. Several criteria suggest arachidonic acid (AA) may mediate depolarization-induced modulation of IR. Previously, free AA has been shown to constitutively inhibit IR in the resting state. Also, depolarization has been reported to stimulate liberation of AA from storage in Aplysia ganglia. Consistent with previous results in neuron R 15, depolarization-induced modulation of IR in giant neurons was dependent on external calcium. Indomethacin and 4-bromophenacylbromide (BPB), pharmacologic agents that activate IR through inhibition of AA turnover, altered the effect of depolarization on IR. In contrast serotonin (5HT), which activates IR through adenosine 3',5'-cyclic monophosphate (cAMP), did not alter the effect of depolarization. Also, extended perfusion with bovine serum albumin (BSA), which strips AA from lipid storage in neurons, decreased the depolarization-induced modulation of IR. We conclude that the calcium influx accompanying depolarization activates the phospholipase responsible for liberation of AA from phospholipid, and the liberated AA then acts to inhibit IR. The molecular mechanism of this AA-mediated inhibition remains to be determined. 4. Depolarization-induced modulation of ICl was also dependent on external calcium but was not affected by BPB and only slightly decreased with indomethacin. This suggested AA was probably not involved in this modulation. However, 5HT opposed the modulation of IC1 induced by previous depolarization, suggesting cAMP may be involved in this effect of depolarization.

Acetophenones↗
PubMed1990

Electrical stimulation of cervical vagal afferents. I. Central relays for modulation of spinal nociceptive transmission.

1. Supraspinal relays for vagal afferent modulation of responses of spinal dorsal horn neurons to 50 degrees C heating of the skin were examined by the use of nonselective, reversible local anesthesia or soma-selective, irreversible neurotoxic damage of neural tissue. Eighty-five neurons were isolated in the lumbar spinal dorsal horn of 80 pentobarbital-anesthetized, paralyzed rats. All neurons studied had receptive fields on the glabrous skin of the plantar surface of the ipsilateral hind paw and responded to mechanical stimuli of both low and high intensity as well as noxious thermal stimulation. 2. Intensity-dependent modulation by vagal afferent stimulation (VAS) of neuronal responses to heating of the skin was established. Responses of 40 units were facilitated by low and inhibited by greater intensities of VAS. Another 36 units were only inhibited by VAS, and four were only facilitated. 3. Local anesthesia of the dorsolateral pons by bilateral microinjections of lidocaine (4%, 0.5 microliter) were made to examine the contribution of this area to VAS-produced spinal modulation. The microinjection of lidocaine bilaterally into the ventral locus coeruleus/subcoeruleus (LC/SC) reversibly and significantly attenuated VAS-produced inhibition of unit responses to heat from 63 to 89% of control and abolished VAS-produced facilitation. The microinjection of lidocaine bilaterally into the dorsal LC had no significant effect on VAS-produced modulation of spinal dorsal horn neurons. 4. Ibotenic acid (10 micrograms, 0.5 microliter) was microinjected into the dorsolateral pons to determine the relative contributions of cell bodies in this area to VAS-produced spinal modulation. Unilateral microinjection of ibotenic acid into the LC/SC ipsilateral to the vagus nerve stimulated had no significant effect on VAS-produced inhibition but significantly attenuated VAS-produced facilitation of unit responses to heat. Bilateral microinjections of ibotenic acid significantly attenuated VAS-produced inhibition of unit responses to heat from 48 to 94% of control. 5. Local anesthesia of the medial rostroventral medulla (RVM), primarily the nucleus raphe magnus (NRM), significantly attenuated VAS-produced inhibition of unit responses to heat from 55 to 87% of control but had no significant effect on VAS-produced facilitation. Microinjection of ibotenic acid into the RVM also significantly reduced VAS-produced inhibition of unit responses to heat. No significant change in VAS-produced spinal modulation was found after lidocaine microinjection into areas dorsal to the NRM, the nucleus raphe pallidus, or the olivary nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Functional connectivity between brain stem midline neurons with respiratory-modulated firing rates.

1. Recent evidence supports the idea that neurons distributed along the midline of the brain stem contribute to the regulation of breathing. This study sought evidence for functional connections between midline neurons with respiratory-modulated firing rates. 2. Experiments were conducted on 38 anesthetized, paralyzed, bilaterally vagotomized, artificially ventilated cats. Planar arrays of tungsten microelectrodes were used to monitor spike trains of two or more midline neurons simultaneously in the regions of n. raphe obscurus, n. raphe pallidus, and n. raphe magnus. Efferent phrenic nerve activity was recorded. Data were analyzed with auto- and cross-correlograms and cycle-triggered histograms. Spike trains of neurons were also tested for respiratory modulation by an analysis of variance with the use of a subjects-by-treatments experimental design. 3. Of 584 neurons studied, 99.1% were tonic, i.e., they had firing probabilities greater than zero in all phases of the respiratory cycle. Fifty-three percent of the neurons had respiratory-modulated firing rates; 223 cells were more active during the expiratory (E) interval; 88 neurons were inspiratory (I)-related. The remaining cells were classified as having no respiratory-related modulation of firing rate (NRR). 4. The spike trains of 210 of 1,078 pairs (19.5%) of brain stem midline neurons exhibited short-time scale correlations indicative of paucisynaptic interactions. Primary cross-correlogram features included 129 central peaks, 45 offset peaks, two central troughs, and 57 offset troughs. Twenty-two of the neuronal pairs analyzed had both offset peaks and troughs. Correlograms from an additional 35 pairs of neurons had multiple peaks and troughs without a significant primary feature. 5. The frequency of correlations for neuron pairs composed of cells with respiratory-modulated firing rates was as follows: E-E, 40/185 (22%); E-I, 23/111 (21%); E-NRR, 45/297 (15%); I-I, 11/25 (44%); and I-NRR, 13/104 (13%). Twenty-two percent of the NRR pairs (79/357) exhibited short-time scale correlations. 6. Thirty pairs of neurons included a cell with an antidromically identified axonal projection extending to at least the third cervical segment. The mean estimated conduction velocity based on the single-site stimulation method was 26.5 +/- 9.9 (SD) m/s. 7. The results provide evidence for inhibitory and excitatory functional connections between midline brain stem neurons. Data support the hypothesis that the respiratory-modulated discharge patterns of midline neurons are, at least in part, a consequence of the synaptic actions of other midline cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1992

Modulation of IK,Ca by phorbol ester-mediated activation of PKC in pleural sensory neurons of Aplysia.

1. The electrophysiological properties of the sensory neurons that mediate withdrawal reflexes in Aplysia are modulated by a number of second messengers. For example, the second messengers adenosine 3',5'-cyclic monophosphate (cAMP) and arachidonic acid modulate the S-K+ current (IK,S) and the calcium-activated K+ current (IK,Ca). Recent evidence suggests that protein kinase C (PKC) may also be an important regulator of cellular plasticity. In the present study we examined the possibility that IK,Ca was modulated by the activation of PKC in the pleural sensory neurons. 2. In voltage-clamped sensory neurons the application of phorbol esters, such as phorbol dibutyrate (PDBu), phorbol myristate (PMA), and phorbol diacetate (PDAc), which activate PKC, caused a dose-dependent increase in a voltage-dependent current with properties that resembled IK,Ca. The inactive isomer of phorbol ester, 4 alpha-phorbol, was without effect. 3. This phorbol ester-sensitive current had the kinetics and pharmacological sensitivity of IK,Ca. The current developed slowly during step depolarizations, showed little inactivation, and was activated at membrane potentials greater than approximately 0 mV. In addition, the current modulated by phorbol esters was blocked by a concentration of tetraethylammonium (TEA) that blocks a component of IK,Ca in the sensory neurons. 4. IK,Ca, which was activated directly by the iontophoretic injection of Ca2+, was also enhanced by PDBu. Moreover, the enhancement of Ca(2+)-elicited responses by PDBu persisted after Ca2+ influx was blocked by cobalt. These results indicate that at least one component of the modulation of IK,Ca by PDBu was independent of the modulation of voltage-dependent Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

High-frequency neurons in the inferior colliculus that are sensitive to interaural delays of amplitude-modulated tones: evidence for dual binaural influences.

1. Localization of sounds has traditionally been considered to be performed by a duplex mechanism utilizing interaural temporal differences (ITDs) at low frequencies and interaural intensity differences at higher frequencies. More recently, it has been found that listeners can detect ITDs at high frequencies if the amplitude of the sound varies and an ITD is present in the envelope. Here we report the responses of neurons in the inferior colliculi of unanesthetized rabbits to ITDs of the envelopes of sinusoidally amplitude-modulated (SAM) tones. 2. Neurons were studied extracellularly with glass-coated Pt-Ir or Pt-W microelectrodes. Their sensitivity to ITDs in the envelopes of high-frequency sounds (> or = 2 kHz) was assessed using SAM tones that were presented binaurally. The tones at the two ears had the same carrier frequency but modulation frequencies that differed by 1 Hz. This caused a cyclic variation in the ITD produced by the envelope. In this "binaural SAM" stimulus, the carriers caused no ITD because they were in phase. In addition to the binaural SAM stimulus, pure tones were used to investigate responses to ipsilateral and contralateral stimulation and the nature of the interaction during binaural stimulation. 3. Neurons tended to display one of two kinds of sensitivity to ITDs. Some neurons discharged maximally at the same ITD at all modulation frequencies > 250 Hz (peak-type neurons), whereas others were maximally suppressed at the same ITD (trough-type neurons). 4. At these higher modulation frequencies (> 250 Hz), the characteristic delays that neurons exhibited tended to lie within the range that a rabbit might normally encounter (+/- 300 microseconds). The peak-type neurons favored ipsilateral delays, which correspond to sounds in the contralateral sound field. The trough-type neurons showed no such preference. 5. The preference of peak-type neurons for a particular delay was sharper than that of trough-type neurons and was comparable to that observed in neurons of the inferior colliculus that are sensitive to delays of low-frequency pure tones. 6. At lower modulation frequencies (< 150 Hz) characteristic delays often lay beyond +/- 300 microseconds. 7. Increasing the ipsilateral intensity tended to shift the preferred delay ipsilaterally at lower (< 250 Hz), but not at higher, modulation frequencies. 8. When tested with pure tones, a substantial number of peak-type neurons were found to be excited by contralateral stimulation but inhibited by ipsilateral stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗