Paul Adams

Stony Brook University | Stony Brook · Department of Neurobiology and Behavior

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 norm...

Learning is thought to occur by localized, activity-induced changes in the strength of synaptic connections between neurons. Recent work has shown that induction of change at one connection can affect changes at others ("crosstalk"). We studied the role of such crosstalk in nonlinear Hebbian learning using a neural network implementation of indepen...

Almost all the information that is needed to specify thalamocortical and neocortical wiring derives from patterned electrical activity induced by the environment. Wiring accuracy must be limited by the anatomical specificity of the cascade of events triggered by neural activity and culminating in synaptogenesis. We present a simple model of learnin...

Recent work on Long Term Potentiation in brain slices shows that Hebb's rule is not completely synapse-specific, probably due to intersynapse diffusion of calcium or other factors. We extend the classical Oja unsupervised model of learning by a single linear neuron to include Hebbian inspecificity, by introducing an error matrix E, which expresses...

Learning is thought to be achieved by the selective, activity dependent, adjustment of synaptic connections. Individual learning can also be very hard and/or slow. Social, supervised, learning from others might amplify individual, possibly mainly unsupervised, learning by individuals, and might underlie the development and evolution of culture. We...

This is the summary of a paper I presented at a Physiological Society meeting in Birmingham, December 18-19, 1974. The paper proposed that local anaesthetics modify the time-course of the synaptic current at the frog neuromuscular junction by transiently blocking the open channel activated by acetylcholine release. This idea built on previous work...

Social, supervised, learning from others might amplify individual, possibly unsupervised, learning by individuals, and might underlie the development and evolution of culture. We studied a minimal model of the interaction of individual unsupervised and social supervised learning by interacting agents. Agents attempted to learn to track a hidden flu...

Input data were generated by linear mixing of independently fluctuating signals. Agents, each a single neuron, attempt to unmix the data and track the hidden signals by Hebbian adjustment of their synaptic weights, either unsupervised or by using observations of the outputs of other agents. Successful learning was made difficult either by using sli...

Unlabelled: The history, content and consequences of the highly-cited 1982 Brain Research paper by Halliwell and Adams are summarized. The paper pioneered the use of the single-electrode voltage clamp in mammalian brain slices, described 2 novel sub-threshold voltage-dependent ionic currents, IM and IQ/H, and suggested that cholinergic inputs "ena...

Hebbian synapses respond to input/output correlations, and thus to input statistical structure. However, recent evidence suggests that strength adjustments are not completely connection-specific, and this “crosstalk” could distort, or even prevent, learning processes. Crosstalk would then be a form of adjustment mistake, analogous to mistakes in po...

Purpose: We previously proposed that Hebbian adjustments that are incompletely synapse specific ("crosstalk") might be analogous to genetic mutations. We analyze aspects of the effect of crosstalk in Hebbian learning using the classical Oja model. Methods: In previous work we showed that crosstalk leads to learning of the principal eigenvector of E...

The origin of life from matter and the subsequent emergence of mind were fundamental events. Our work is based on the idea that the chemi-cal/genetic/mathematical framework developed over the last 150 years to explain the first is conceptually similar to the neural/psychological/mathematical framework needed to understand the second. First we outli...

The neocortex is widely believed to be the seat of intelligence and "mind". However, it's unclear what "mind" is, or how the special features of neocortex enable it, though likely "connectionist" principles are involved *A. The key to intelligence1 is learning relationships between large numbers of signals (such as pixel values), rather than memori...

Recent work on long term potentiation in brain slices shows that Hebb's rule is not completely synapse-specific, probably due to intersynapse diffusion of calcium or other factors. We previously suggested that such errors in Hebbian learning might be analogous to mutations in evolution. We examine this proposal quantitatively, extending the classic...

We propose that certain brain systems, such as those of neocortex, exploit a fusion of ideas from neural networks and evolutionary computation, and that several previously puzzling features of thalamocortical circuitry and physiology can be understood as consequences of this fusion. The starting point is a consideration of anatomical errors in the...

Recent work in hippocampus suggests that correlation-based synaptic strengthening occurs both imprecisely and digitally. We explore this in a model in which synapses are created according to a "tness function and are occasionally incorrectly placed. Synapses spread beyond the high "tness (w . ) area to lower "tness (w 1 ) areas to an extent that de...

It is proposed that vertebrate brains, especially those of mammals, operate according to an algorithm subsumable as "synaptic Darwinism". The key postulate is that genes and synapses follow the same rules, because they act as autocatalytic, hypercyclic, units of selection. Synapses replicate by quantally strengthening, and mutate by connecting new...

Thalamic neurons have two firing modes: "tonic" and "burst." During burst mode, both low-threshold (LT) and high-threshold (HT) calcium channels are activated, while in tonic mode, only the HT-type of calcium channel is activated. The calcium signals associated with each firing mode were investigated in rat thalamic slices using whole cell patch cl...

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, an...

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, an...

Regulation of M current (lM) by intracellular free calcium was studied in dissociated bullfrog sympathetic ganglion B cells using whole-cell recording, intracellular perfusion, and confocal calcium imaging. BAPTA (20 mM) and appropriate amounts of calcium were added to pipette solutions to clamp calcium at different levels. A high concentration of...

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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: 'fa...

1. Calcium release and sequestration were studied in whole-cell voltage-clamped bull-frog sympathetic neurones by image analysis of Fura-2 signals. 2. Application of caffeine (10 mM) to cells voltage clamped at -38 mV caused a rapid increase in intracellular calcium concentration ([Ca2+]i) to a mean value of 352 +/- 33 nM, which activated an outwar...

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...

Neurons of the cat's dorsal lateral geniculate nucleus were recorded intracellularly to study the contribution of N-methyl-D-aspartate (NMDA) receptors to excitatory postsynaptic potentials (EPSPs) and low-threshold calcium spikes. EPSPs were evoked by stimulation of retinogeniculate axons in the optic tract and/or corticogeniculate axons in the op...

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 spherica...

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 config...

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...

Excerpt In the nervous system, a multiplicity of neurotransmitters are capable of activating the phosphatidylinositol (PtdIns) system, i.e., of accelerating the enzymatic breakdown of membrane phosphatidylinositide bisphosphate (PtdInsP2) to inositol 1,4,5-tris-phosphate (Ins[1,4,5]P3) and diacylglycerol (DAG) (Fisher and Agranoff 1986; Berridge 19...

Communication within the nervous system is governed by the frequency and pattern of action potential discharges, and hence by variations in ionic current flow across the outer cell membrane. Thus, if a chemical neurotransmitter is to change the electrical activity of a recipient neurone, its biochemical action on the receptor haB to be transduced i...

This chapter compares and contrasts the actions of neuropeptides with “classical” neurotransmitters to discuss how cells are organized to respond to different messages. The number of known (or suspected) transmitters, and of known (or suspected) cellular actions of transmitters, is increasing without apparent limit. It is important to see whether a...

1. Effects of bath-applied phorbol dibutyrate (PDBu) on M currents (IM) and on the inhibition of IM by muscarine and luteinizing hormone-releasing hormone (LHRH) were recorded in voltage-clamped bullfrog lumbar sympathetic ganglion cells. 2. PDBu (0.1-30 microM) produced a slowly developing, irreversible and partial (less than or equal to 60%) inhi...

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 expon...

In this communication we describe a technique for rapidly exchanging solutions bathing excised membrane patches, and present examples of its implementation using both outside-out and inside-out patches. The ability to make step changes in the concentration of channel-activating ligands (e.g., acetylcholine, calcium) offers a novel and direct means...

Bullfrog ganglia contain two classes of neurone, B and C cells, which receive different inputs and exhibit different slow synaptic potentials. B cells, to which most effort has been directed, possess slow and late slow EPSPs. The sEPSP reflects a muscarinic action of acetylcholine released from boutons on B cells, whereas the late sEPSP is caused b...

A single-electrode voltage-clamp technique was employed on in vitro hippocampal slices to examine the membrane current responsible for the slow afterhyperpolarization (AHP) in CA1 pyramidal cells. This was achieved by using conventional procedures to evoke an AHP in current clamp, followed rapidly by a switch into voltage clamp (hybrid clamp). The...

This chapter reviews what is known of the voltage-dependent conductances of three classes of vertebrate nerve cell, as assessed by somatic voltage clamping. These classes are: (1) bullfrog paravertebral sympathetic ganglion cells; (2) rodent superior cervical sympathetic ganglion cells; and (3) rodent hippocampal pyramidal cells. Of these, bullfrog...

Healthy bullfrog sympathetic ganglion cells often show a two-component afterhyperpolarization (AHP). Both components can be reduced or abolished by adding Ca-channel blockers or by removing external Ca. Application of a single electrode "hybrid clamp"--i.e., switching from current- to voltage-clamp at the peak of the AHP, reveals that the slow AHP...

The existence of a calcium activated potassium current (Ic) in the somata of vertebrate sympathetic ganglion cells was postulated to account for the calcium-sensitive spike after-hyperpolarizations present in these cells [19,22,26]. We have studied Ic in bullfrog ganglion cells more directly by using various voltage-clamp techniques, partly in orde...

Two recent reports in Nature illustrate the power and precision of the new patchclamp techniques for characterizing ion channels activated by transmitter molecules 1,2. The transmitters involved, GABA, glycine and glutamate, are thought to be among the most important of those used in the mammalian CNS. The inhibitory transmitters GABA and glycine w...

Bullfrog sympathetic ganglion neurons have a "late, slow" excitatory postsynaptic potential (EPSP) that is mediated by a peptide similar to mammalian luteinizing hormone-releasing hormone (M-LHRH) (Jan, Y. N., L. Y. Jan, and S. W. Kuffler (1979) Proc. Natl. Acad. Sci. U. S. A. 76: 1501-1505). On biochemical evidence (Eiden, L. E., E. Loumaye, N. Sh...

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. Ti...

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, du...

Until quite recently the electrical behaviour of vertebrate nerve cells revealed by microelectrode recordings has been largely explained in terms of quantitative data and concepts obtained with molluscan neurones. Attempts are now being made in several laboratories to characterize the voltage-dependent currents of vertebrate neurones themselves. So...

1. Slow muscarinic excitatory post-synaptic currents (slow e.p.s.c.s) generated by preganglionic nerve stimuli were recorded in voltage-clamped bullfrog sympathetic neurones. 2. IM--an outward, voltage-dependent, K+-current--was inhibited during the slow e.p.s.c., and membrane conductance was reduced in a voltage-dependent manner. 3. The slow e.p.s...

1. The effects of muscarinic agonists, luteinizing hormone-releasing hormone (LHRH) analogues, uridine triphosphate (UTP) and divalent cations on K(+)-currents in voltage-clamped bullfrog sympathetic neurones have been studied.2. Muscarine (1-10 muM), D-ala(6) LHRH (1-5 muM), UTP (50-100 muM) and Ba(2+) (1-4 mM) selectively depressed the M-current...

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 resemble...

1. Bullfrog lumbar sympathetic neurones were voltage-clamped in vitro through twin micro-electrodes. Four different outward (K(+)) currents could be identified: (i) a large sustained voltage-sensitive delayed rectifier current (I(K)) activated at membrane potentials more positive than -25 mV; (ii) a calcium-dependent sustained outward current (I(C)...

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 calciu...

A description is given of methods for voltage clamping and for studies of the several varieties of K-currents occurring in sympathetic neurons. Conclusions were derived chiefly from experiments conducted on bullfrog lumbar paravertebral sympathetic ganglia but observations made were compared with results obtained from studies of neurons of the rat...

Many neurones, when depolarized, exhibit two components of outward K+ current-the voltage-sensitive delayed rectifier current originally described in squid axons by Hodgkin and Huxley1, and an additional current triggered by the entry of Ca2+ ions2. These two currents have been termed IK and IC, respectively3. Previous experiments have indicated th...

This chapter describes the calcium current of a vertebrate neuron. The existence of calcium currents in vertebrate sympathetic ganglion cells has been known for some time. The chapter discusses a study to provide an initial characterization of calcium current kinetics in sympathetic neurons. Bullfrog neurons were cesium loaded using a modified nyst...

Experiments of voltage-clamped bullfrog sympathetic neurons suggest that the "slow depolarization" produced by orthodromic stimulation, by muscarinic agonists, or by the peptide luteinizing hormone-releasing hormone (LHRH), results from the suppression of a time- and voltage-dependent outward K+ current, the "M current" (IM). This current is activa...

Abdominal stretch receptor neurons of Procambarus clarkii were voltage clamped with two microelectrodes, and the synaptic currents set up by stimulating the inhibitory axons, or by rapid bath application of gamma-aminobutyric acid (GABA), were recorded. The inhibitory postsynaptic current (IPSC) decay was exponential, the time constant of decay bei...

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...

The effects of quinacrie on end-plate currents (e.p.c.s.), miniature end-plate currents (m.e.p.c.s.) and ionophoretic responses at voltage clamped frog end-plates were investigated. A quinacrine concentration (2 μm) that by itself has little effect on m.p.e.c.s. will considerably attenuate responses to bath applied carbachol. The combined effect of...

1. The effects of quinacrine on the relaxation of the agonist-induced currents in response to a voltage step were investigated at voltage clamped frog end-plates. A fast perfusion technique allowed the application of known concentrations of the agonist acetylcholine (ACh) or carbachol to end-plate viewed with Nomarski optics. 2. In the presence of...

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. T...

Cholinergic excitation of vertebrate neurones is frequently mediated through the action of acetylcholine on muscarinic (atropine-sensitve) receptors. This type of excitation differs substantially from the better known nicotinic excitation. One difference is that, instead of an increased membrane conductance, a decreased conductance (to K+ ions) fre...

1. Extrasynaptic GABA-receptors occur on both neurone somata and unmyelinated axons in the mammalian peripheral nervous system. Activation of these receptors leads to depolarization, reduced spike amplitude and slowed conduction, probably mediated through increased Cl- conductance. 2. GABA also depolarizeds preganglionic nerve terminals in the rat...

1. Local conductance changes produced by various bath-applied agonists at frog end-plate membrane were measured using focal recording of extracellular potential in voltage-clamped muscle fibres. The potential difference between a focal micropipette placed on the nerve terminal and another micro-pipette placed on or near inactive membrane was taken...

Miniature endplate currents, endplate current fluctuations ("membrane noise"), and voltage-jump current relaxations were studied in voltage-clamped frog muscle fibers during decamethonium action. All three types of experiments revealed two kinetic processes controlling the opening of endplate channels, one that reflects agonist action and another t...

It was during the first half of the present century that the ideas of chemical transmission between neurones were first put forward, and subsequently investigated by the likes of Dale and Loewi. Since that time various efforts have gone into unravelling the molecular mechanisms involved in the processes of neurotransmission. In this article Paul Ad...

GRÜNHAGEN and Changeux have shown1,2 that Torpedo membrane fragments stained with the antimalarial, quinacrine, show a rapid increase in fluorescence after mixing with cholinergic agonists (see ref. 3). These authors suggest that the fluorescence intensity of quinacrine associated with cholinergic receptors increases during the transition of the re...

1. The effect of step changes in membrane potential on the end-plate conductance change produced by bath-applied suberyldicholine was studied in voltage-clamped frog muscle fibres. 2. The suberyldicholine-induced conductance increased exponentially from its previous equilibrium level to a new equilibrium level following a step hyperpolarization. 3....

1. In the absence of procaine the end-plate conductance evoked by suberyldicholine increases exponentially to a new level following a step hyperpolarization. In the presence of procaine the suberyldicholine-evoked conductance first rapidly decreases and then slowly increases following a hyperpolarizing step. The fast relaxation has a time constant...

1. The actions of amylobarbitone, thiopentone, methohexitone and methyprylone at voltage-clamped frog end-plates were studied. 2. In the presence of barbiturates the conductance change evoked by an iontophoretic carbachol application was reduced by a prepulse of carbachol. The extra inhibition evoked by a prepulse disappeared exponentially with a t...

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 b...

The conductance increment produced at voltage clamped frog endplates by various agonists, applied either iontophoretically or in the bath, increases exponentially with membrane hyperpolarisation, an e-fold change being obtained with shifts of the order of 100 mV. The voltage dependency of this increase is the same for different, but low, agonist co...

The agonist concentration—endplate conductance relation was examined for a number of agonists (such as carbachol, alkyl trimethylammonium salts, choline and decamethonium). The endplate current evoked varied asI max [a/(a+K)]2, wherea is the agonist concentration andI max andK are agonist-specific parameters. This finding suggests that the endplate...

The effect of bath applied agonists and reversible and irreversible antagonists upon the endplate currents produced by agonists applied either iontophoretically or in the bath was studied quantitatively. Agonist-agonist interaction (both potentiation and inhibition) can be accounted for satisfactorily by postulating independent binding and conforma...

The onset and offset of desensitization produced by carbachol and hexyl and heptyl TMA at voltage-clamped frog endplates were studied. Desensitization onsets exponentially with a rate constant which is proportional to the agonist concentration. The proportionality constant varies with the agonist used. The plateau current finally attained falls ste...

1. Responses of single ganglion cells in the isolated rat superior cervical ganglion to gamma-aminobutyric acid (GABA) applied via the bathing medium were recorded using intracellular micro-electrodes. 2. GABA produced a large fall in cell input resistance, frequently to immeasurable levels. In thirteen cells showing a modest response to 100 muM GA...

Crab nerve and frog sartorius muscle stained with 1-anilinonaphthalene-β-sulphonate (ANS),show transient increases in fluorescence during action potentials,and transient decreases during imposed hyperpolar isations. Both changes were of the order of 10−4 of the background fluorescence. The time-course of both optical and electrical responses were s...

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, an...