Hebbian learning from higher-order correlations requires crosstalk minimization.

Activity-dependent synaptic plasticity should be extremely connection specific, though experiments have shown it is not, and biophysics suggests it cannot be. Extreme specificity (near-zero "crosstalk") might be essential for unsupervised learning from higher-order correlations, especially when a neuron has many inputs. It is well known that a normalized nonlinear Hebbian rule can learn "unmixing" weights from inputs generated by linearly combining independently fluctuating nonGaussian sources using an orthogonal mixing matrix. We previously reported that even if the matrix is only approximately orthogonal, a nonlinear-specific Hebbian rule can usually learn almost correct unmixing weights (Cox and Adams in Front Comput Neurosci 3: doi: 10.3389/neuro.10.011.2009 2009). We also reported simulations that showed that as crosstalk increases from zero, the learned weight vector first moves slightly away from the crosstalk-free direction and then, at a sharp threshold level of inspecificity, jumps to a completely incorrect direction. Here, we report further numerical experiments that show that above this threshold, residual learning is driven instead almost entirely by second-order input correlations, as occurs using purely Gaussian sources or a linear rule, and any amount of crosstalk. Thus, in this "ICA" model learning from higher-order correlations, required for unmixing, requires high specificity. We compare our results with a recent mathematical analysis of the effect of crosstalk for exactly orthogonal mixing, which revealed that a second, even lower, threshold, exists below which successful learning is impossible unless weights happen to start close to the correct direction. Our simulations show that this also holds when the mixing is not exactly orthogonal. These results suggest that if the brain uses simple Hebbian learning, it must operate with extraordinarily accurate synaptic plasticity to ensure powerful high-dimensional learning. Synaptic crowding would preclude this when inputs are numerous, and we propose that the neocortex might be distinguished by special circuitry that promotes extreme specificity for high-dimensional nonlinear learning.

Subcellular calcium transients visualized by confocal microscopy in a voltage-clamped vertebrate neuron.

Confocal laser-scanned microscopy and long-wavelength calcium (Ca2+) indicators were combined to monitor both sustained and rapidly dissipating Ca2+ gradients in voltage-clamped sympathetic neurons isolated from the bullfrog. After a brief activation of voltage-dependent Ca2+ channels, Ca2+ spreads inwardly, and reaches the center of these spherical cells in about 300 milliseconds. Although the Ca2+ redistribution in the bulk of the cytosol could be accounted for with a radial diffusion model, local nonlinearities, suggesting either nonuniform Ca2+ entry or spatial buffering, could be seen. After electrical stimulation, Ca2+ signals in the nucleus were consistently larger and decayed more slowly than those in the cytosol. A similar behavior was observed when release of intracellular Ca2+ was induced by caffeine, suggesting that in both cases large responses originate from Ca2+ release sites near or within the nucleus. These results are consistent with an amplification mechanism involving Ca2(+)-induced Ca2+ release, which could be relevant to activity-dependent, Ca2(+)-regulated nuclear events.

Modulation of M-current by intracellular Ca2+.

IM is a voltage- and time-dependent K+ current that is suppressed by muscarinic receptor activation. IM augmentation following agonist washout was blocked by heavily buffering [Ca2+]i using BAPTA. Although IM is not primarily Ca2+ dependent, small increases in [Ca2+]i by photolysis of the "caged" Ca2+ chelator nitr-5 or by evoking action potentials augmented, while larger increases inhibited, IM. Raising [Ca2+]i for prolonged periods, by nitr-5 photolysis, reduced its sensitivity to agonist, leaving a poorly reversible response. These results suggest that IM can be regulated by physiologically relevant changes in [Ca2+]i, placing IM in a unique position to modulate cell excitability.

Uptake of nitrate, ammonium and glycine by plants of Tasmanian wet eucalypt forests.

A central assumption of ecosystem N cycling has been that organic N must be converted to inorganic N to be available for plant uptake, but this has been questioned by recent studies. We examined uptake of nitrate, ammonium and the amino acid glycine in three species from Eucalyptus obliqua L'Her. wet forest in Tasmania, south-eastern Australia, to test the hypothesis that all three species can take up glycine, and to compare rates of glycine uptake with rates of uptake of nitrate and ammonium uptake. The alternative hypothesis that species vary in their preference for nitrate, ammonium and glycine ("niche differentiation") was also examined. Measurements were made on the canopy dominant Eucalyptus obliqua, and two rain forest tree species found in the understory or as sub-dominants of the canopy, Nothofagus cunninghamii (Hook.) Oerst. and Phyllocladus aspleniifolius (Labill.) Hook.f. Nitrogen uptake was examined in situ with attached roots placed in uptake solutions containing equimolar concentrations (100 micromol l(-1)) of (15)N-nitrate, (15)N-ammonium and 2-(13)C(2) (15)N-glycine. Species did not differ in their preference for different forms of N (species x N form interaction, P > 0.05), and thus there was no evidence of niche differentiation. In all species, rates of uptake were highest for ammonium (11 +/- 5 micromol g(DM) (-1) h(-1); mean +/- SD, n = 108), uptake of glycine occurred at less than half this rate (4.4 +/- 2.6 micromol g(DM) (-1) h(-1)), whereas uptake of nitrate occurred at one-tenth of this rate (0.9 +/- 1.2 micromol g(DM) (-1) h(-1)). The strong positive relationship between (15)N and (13)C uptake indicated that at least 72% of glycine-N was taken up intact. These findings indicate the potential for considerable uptake of organic N in the field.

Ca-activated potassium current in vertebrate sympathetic neurons.

Ca-activated K-currents (IC) in sympathetic neurones have been triggered by intracellular Ca-injection or by activating ICa. IC is strongly voltage-dependent, with a peak slope of 11 mV/e-fold depolarization above -50 mV. Relaxation, fluctuation and single channel analysis suggests this to result from voltage-dependent opening and closing rates. Time-constants for channel opening and closing are about 15 msec near zero mV. Single channel conductance is about 100 pS. Currents can be blocked by TEA. IC is activated very rapidly (less than or equal to 5 msec) and sometimes transiently by a depolarizing voltage-step. It is suggested that IC contributes to both spike repolarization and spike after-hyperpolarization. Spontaneous miniature ICs have also been recorded, probably activated by the release of packets of intracellular Ca.

Bradykinin inhibits a potassium M-like current in rat pheochromocytoma PC12 cells.

We studied the action of bradykinin (BK) on ionic currents in fused pheochromocytoma PC12 cells under voltage-clamp in whole-cell mode, and on intracellular calcium using fura-2 BK induced the development of an outward current associated with an increase in intracellular calcium, followed by inhibition of an M-like current. The outward current was blocked by (+)-tubocurarine, and prevented when the calcium BAPTA or high concentrations of inositol 1,4,5-triphosphate were introduced into the cell, whereas the M-like current and its inhibition by BK remained unaffected. The protein kinase activator phorbol 12,13 dibutyrate partially reduced the M-current. M-current density did not substantially change after prolonged treatment with nerve growth factor.

A G Protein Mediates the Inhibition of the Voltage-Dependent Potassium M Current by Muscarine, LHRH, Substance P and UTP in Bullfrog Sympathetic Neurons.

The involvement of G proteins in the transduction mechanism of M current (Im) inhibition by extracellular ligands in bullfrog sympathetic neurons was examined using the hydrolysis resistant nucleotide analogues GTPgammaS and GDPbetaS. Im was recorded in large (40 - 60 microm) isolated neurons using the patch-clamp technique in the whole-cell configuration, as well as in neurons from the intact ganglion impaled with conventional microelectrodes. In whole-cell recordings Im could be recorded without significant loss for 1 h or more provided ATP was present in the patch pipette. Muscarine, D-Ala6-LHRH, substance P and UTP reversibly inhibited Im in isolated control neurons, with full and rapid recovery of the current following agonist washout. Dialysis of isolated neurons with various concentrations of GTPgammaS (1 - 100 microM) affected, in a dose-dependent manner, the recovery of Im after its inhibition by brief agonist application. With 50 microM GTPgammaS, Im inhibition became completely irreversible. Similarly, the reversibility of Im inhibition by muscarine was reduced or abolished by the iontophoretic injection of GTPgammaS through a second microelectrode into neurons of the intact ganglion. GTPgammaS by itself caused a slow, agonist-independent suppression of Im in dialysed neurons, thus mimicking agonist action. Dialysis of isolated neurons with GDPbetaS (100 - 500 microM) attenuated by half or more the magnitude of Im inhibition by agonist as compared to control neurons. In addition, GDPbetaS attenuated the response of a given neuron to muscarine and D-Ala6-LHRH, and caused slow increase of Im, as a function of dialysis time. Incubation (2 - 72 h, 4 - 36 degrees C) of isolated neurons or intact ganglions with activated pertussis toxin had no effect on the response to muscarine. Toxin injections to experimental animals were equally ineffective. In contrast to Im, the additional inward current with increase in conductance induced by muscarine and D-Ala6-LHRH reversed with agonist washout in GTPgammaS-dialysed neurons, although more slowly than in control neurons. The results in this study indicate that a G protein, possibly pertussis toxin-insensitive, provides a common coupling step linking muscarinic, substance P, D-Ala6-LHRH and UTP receptors to the inhibition of M current.

Multiple kinetic states underlying macroscopic M-currents in bullfrog sympathetic neurons.

M-current is a time- and voltage-dependent potassium current which is suppressible by muscarinic receptor activation. We have used curve fitting and noise analysis to determine if macroscopic M-currents deviate from a previously predicted simple two-state kinetic scheme. The M-current was best described by three kinetically distinct components: 'fast' (tau 0), 'intermediate' (tau 1) and 'slow' (tau 2) time constants. The 'fast' (tau 0) and 'intermediate' (tau 1) components were identified from the spectra of M-current noise at potentials positive to the cells' resting membrane potential. The 'intermediate' (tau 1) and 'slow' (tau 2) components were seen by curve fitting M-current deactivation currents. The 'intermediate' (tau 1) time constant was voltage dependent (decreasing e-fold in 23 mV), but voltage dependence of the 'fast' (tau 0) and 'slow' (tau 2) components was not obvious. All kinetic components were sensitive to muscarine, with the 'intermediate' (tau 1) and 'slow' (tau 2) being equally so. These data suggest that all components may derive from the same channel population, and that the M-channel may have at least four kinetic states.

Factors affecting outcome of coronary reperfusion with intracoronary streptokinase in acute myocardial infarction.

Aggressive interventional therapy in acute myocardial infarction (AMI) is expensive, time-consuming and not without significant risk. To determine which patients are most likely to benefit from such therapy, the effects of patient age, reperfusion success, admission left ventricular (LV) function, infarct location, admission clinical class, time from onset of pain to reperfusion and admission electrocardiographic findings on the outcome of coronary reperfusion in AMI were assessed in 292 prospectively studied, sequential patients from August 1980 to January 1984. Two hundred ten patients received intracoronary streptokinase (SK) therapy on admission and 82 patients, who either refused the protocol or met exclusion criteria, served as control subjects. Patients older than 65 years showed little improvement in 1-year mortality risk and no significant improvement in LV function during hospitalization after treatment with intracoronary SK. The remaining patients, 178 treated with SK and 48 control, were well matched and served as the basis for further comparisons. In this subgroup of patients, reperfusion success was associated with improved survival and LV function (mortality rate 3%, vs 17% in control subjects; increase in ejection fraction [EF] 18% vs 4%). Patients with an EF of less than 45% on admission showed a 21 +/- 30% increase in EF, compared with an increase in control subjects of 8 +/- 19%, and a lower 1-year mortality rate than controls (6% vs 21%, p = 0.01). Patients with anterior AMI had a significant increase in EF in the SK group (22 +/- 31%) and lower mortality compared with control subjects (5% vs 25%, p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of agonist conductance changes during hyperolarization at frog endplates.

The effect of rapid hyperpolarization on acetylcholine- or carbachol-induced currents was studied at voltage clamped frog endplates. Following a hyperpolarizing step the agonist-induced conductance increased approximately exponentially to a new level. The rate constant for this process was smaller during hyperpolarization or lowered temperature, and was also smaller for acetylcholine than for carbachol. The results are interpreted in terms of a potential-dependent conformational change of the receptor.

A comparison of the time course of excitation and inhibition by iontophoretic decamethonium in frog endplate.

1 The depolarization of frog endplate by a brief iontophoretic application of decamethonium was slower in time course than the inhibition of a long carbachol response produced by the same decamethonium pulse, or than the excitation produced by a brief equipotent carbachol pulse. 2 The delay between the peak inhibition and peak excitation produced by decamethonium, about 50 ms, is too great to be explained by slow receptor activation kinetics, since Katz & Miledi (1973) have shown that the lifetime of decamethonium-activated receptors is only 0.25 milliseconds. 3 If doses of carbachol and decamethonium are adjusted to give response amplitudes in the ratio corresponding to the ratio of their presumed maximum responses, then there is little difference in the time courses of the responses. 4 This observation, together with the finding that increasing the dose applied slows the decamethonium response much more than the carbachol response, suggests that a decamethonium response contains contributions from a much wider area of receptive membrane than does a carbachol response of equal amplitude. 5 Simulation shows that these geometrical effects are sufficient to account for the rapidity of inhibition compared to excitation without postulating slow receptor kinetics. 6 It is pointed out that similar effects may account for certain results obtained in iontophoretic studies of desensitization.

Luteinizing hormone-releasing factor and muscarinic agonists act on the same voltage-sensitive K+-current in bullfrog sympathetic neurones.

The effect of bath-applied luteinizing hormone-releasing factor (LHRF) was recorded in voltage-clamped bullfrog lumbar sympathetic neurones. At a holding potential of -- 30 mV, LHRF induced a steady inward (depolarizing) current and reduced membrane conductance; at -- 60 mV LHRF produced negligible inward current and much less conductance change. The effects of LHRF were accompanied by a reduced amplitude of the slow current relaxations following hyperpolarizing and depolarizing commands, without prominent change in their time-course. This suggests a selective depression of the voltage-sensitive outward K+-current which is suppressed by muscarinic agonists.

Substance P inhibits the M-current in bullfrog sympathetic neurones.

Substance P (SP, 2.5-10 microM) was applied by rapid bath perfusion to bullfrog lumbar sympathetic neurones in vitro, voltage-clamped through a single micro-electrode. In unclamped cells, SP produced a depolarization accompanied by an increase in apparent input resistance. Under voltage-clamp a voltage-dependent inward current was induced by SP, during which the time-dependent relaxations induced by square voltage commands were inhibited. It is concluded that SP inhibits the M-current (IM), a species of voltage-dependent K+-current, and that IM-inhibition was the primary cause of the inward current and membrane depolarization in the cells tested.

Peripheral pulmonary artery aneurysm in a patient with limited respiratory reserve: controlled resection using cardiopulmonary bypass.

Pulmonary artery aneurysms are rare lesions for which operative management is not frequently undertaken. When operation is indicated, central lesions involving the pulmonary trunk, right main pulmonary artery, or left main pulmonary artery are repaired using cardiopulmonary bypass. Peripheral aneurysms in segmental intrapulmonary arteries have been managed most frequently by lobectomy, but occasionally by aneurysmectomy and pulmonary arterial repair. We used cardiopulmonary bypass for peripheral pulmonary aneurysmectomy in a patient with limited respiratory reserve because he had undergone prior contralateral bilobectomy; this allowed controlled resection while preserving a maximal amount of pulmonary parenchyma.

Traumatic aortic transections: eight-year experience with the "clamp-sew" technique.

BACKGROUND: Because traumatic aortic transection is associated with high mortality rates, great debate exists about the appropriate operative technique for treatment of patients who have acute traumatic aortic transection. METHODS: To determine the safety and efficacy of the "clamp-sew" method, we retrospectively reviewed our 8-year experience treating 75 patients who had aortic injuries secondary to blunt trauma. Seventy-one of these patients were treated surgically. The clamp-sew method was used in all of these operations. RESULTS: Aortic cross-clamp time averaged 24 minutes (range, 14 to 36 minutes), with 4/71 having times in excess of 30 minutes. One patient (clamp time, 28 minutes) became paraplegic. Significant associated injuries were seen in 51/75 patients (48/71 patients with operation), including intrathoracic (35 patients), orthopedic (28 patients), intraabdominal (24 patients), and central nervous system (17 patients) damage. No patient died within 24 hours of operation. Overall 30-day mortality was 12% (9/75), with 7/9 having two or more aforementioned associated injuries. Of these 7, 5 had central nervous system injuries. Two of 9 died within 30 days without two or more associated injuries: 1 Jehovah's Witness of low hemoglobin, and 1 patient of sepsis. CONCLUSIONS: Although any of several maneuvers may be appropriate in managing traumatic aortic injuries, the simple "clamp-sew" technique is a safe and effective method for the treatment of traumatic aortic transections.

Durability and low thrombogenicity of the St. Jude Medical valve at 5-year follow-up.

Between November, 1978, and December, 1983, 736 patients had valve replacement with the St. Jude Medical valve prosthesis. There were 478 patients with aortic valve replacement (AVR), 188 with mitral valve replacement (MVR), 63 with double valve replacement, and 7 with tricuspid valve replacement (they were not included in this study). The mean age at the time of operation was 46.7 years for patients having AVR and 48.6 years for those having MVR and AVR + MVR. Follow-up totaled 1,116 patient-years (range, 4 to 82 months). Early (30-day) mortality was lowest for isolated MVR (2.3%) and AVR (3.7%), and increased with reoperation or when associated procedures were combined with valve replacement. Patients undergoing reoperation or having associated procedures made up 49% of the AVR and 54% of the MVR groups. All patients were advised of the need for long-term anticoagulation with warfarin sodium. Nine patients (7 with AVR, 1 with MVR, 1 with AVR + MVR) had suspected or confirmed episodes of systemic thromboembolism, a linearized incidence of 0.99% per patient-year for AVR, 0.36% per patient-year for MVR, and 0.98% per patient-year for AVR + MVR. Eight patients with AVR underwent reoperation for prosthetic valve endocarditis (5 of the 8 patients had endocarditis prior to initial valve replacement). There were no instances of structural valve failure. There were 37 late deaths. Actuarial survival at 5 years (excluding early mortality, 95% confidence limits) was 89.8% for AVR, 84.8% for MVR, and 95.2% for AVR + MVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of calcium current in rat sympathetic neurons by norepinephrine.

Inward voltage-dependent calcium currents were recorded from clamped rat sympathetic ganglion cells using either one or two microelectrodes. Suppression of potassium current was achieved by applying tetraethylammonium (TEA) externally and TEA plus cesium internally. Peak ICa was observed at 0 mV. ICa was abolished by perfusing cadmium or low calcium medium. ICa was reduced by adding norepinephrine (1-50 micrometers). This effect was not accompanied by any major change in the voltage sensitivity or time course of the residual calcium current. It is suggested that norepinephrine acts by reducing the number of available calcium channels.

Voltage-clamp analysis of muscarinic excitation in hippocampal neurons.

Pyramidal cells in the CA1 field of guinea pig hippocampal slices were voltage-clamped using a single microelectrode, at 23-30 degrees C. Small inwardly relaxing currents triggered by step hyperpolarizations from holding potentials of -80 to -40 mV were investigated. Inward relaxations occurring for negative steps between -40 mV and -70 mV resembled M-currents of sympathetic ganglion cells: they were abolished by addition of carbachol, muscarine or bethanechol, as well as by 1 mM barium; the relaxations appeared to invert at around -80 mV; they became faster at more negative potentials; and the inversion potential was shifted positively by raising external K+ concentration. Inward relaxations triggered by steps negative to -80 mV, in contrast, appeared to reflect passage of another current species, which has been labelled IQ. Thus IQ did not invert negative to -80 mV, it was insensitive to muscarinic agonists or to barium, and it was blocked by 0.5-3 mM cesium (which does not block IM). Turn-on of IQ causes the well known droop in the hyperpolarizing electrotonic potential in these cells. The combined effects of IQ and IM make the steady-state current-voltage relation of CA1 cells slightly sigmoidal around rest potential. It is suggested that activation of cholinergic septal inputs to the hippocampus facilitates repetitive firing of pyramidal cells by turning off the M-conductance, without much change in the resting potential of the cell.

Spontaneous miniature outward currents in cultured bullfrog neurons.

Spontaneous miniature hyperpolarizations were observed in cultured bullfrog neurons. Depolarization increased the frequency and amplitude of the events. Under voltage-clamp, these events were manifested as spontaneous miniature outward currents of SMOCs which were usually less than 2 nA, had a rapid rising phase and a slower voltage-dependent exponential decay. Analysis of inter-event intervals suggested that SMOCs occurred randomly, while analysis of their amplitudes yielded exponential amplitude distributions. Mean SMOC amplitudes and SMOC frequency increased with depolarization, even with 100 microM CdCl2 present. Time constants of SMOC decay resembled time constants obtained from voltage-jump experiments on Ca2+-loaded cells, and together with the sensitivity of SMOCs to tetraethyl ammonium (TEA), suggested that SMOCs are due to activation of fast Ca2+-gated potassium channels. We propose that a SMOC occurs when 10-5000 of these channels are activated by punctate intracellular Ca2+ release.

Who do barium ions imitate acetylcholine?

The action of 1-4 mM barium on bullfrog sympathetic ganglion cells was studied using voltage clamp. Barium imitated the action of muscarine, causing depolarization, increased input resistance, tendency to repetitive firing, and a specific inhibition of a slow small outward current termed the M current. Barium did not produce significant short-term inhibition of three other outward currents; the delayed rectifier, the calcium-dependent K current, and the A current.