L-prolyl-L-arginyl-glycineamide induces memory enhancement in chicks

Two-day-old chicks were injected either intraventricularly or intraperitoneally with saline or a L-prolyl-L-arginyl-glycineamide solution. This C-terminal tripeptide of arginine vasopressin produced dose dependent enhancement effects when injected centrally but not peripherally. Physical debilitation and/or aversive effects of the peptide were eliminated as the cause of the decreased responding noted in memory enhancement studies using this avoidance paradigm. Possible memory mechanisms are discussed in light of this peptide's relationship to vasopressin, vasotocin, and L-propyl-L-leucyl-glycineamide.     

Intersensory Interactions in Hermissenda

Hair cells of the Hermissenda statocyst respond to photic stimulation. This response requires the presence of at least one of the two eyes. Two principal hair cell responses to light were observed. The activity of photoreceptors in response to a light step is interrupted during firing of contralateral hair cells. The intersensory interactions between the statocyst and visual pathway underlying these responses were examined with simultaneous intracellular recordings. Evidence is presented that the statocyst of Hermissenda is an important channel for visual information.     

Responses of Photoreceptors in Hermissenda

The five photoreceptors in the eye of the mollusc Hermissenda crassicornis respond to light with depolarization and firing of impulses. The impulses of any one cell inhibit other cells, but the degree of inhibition differs in different pairs. Evidence is presented to show that the interactions occur at terminal branches of the photoreceptor axons, inside the cerebropleural ganglion. Properties of the generator potential are examined and it is shown that the depolarization develops in two phases which are affected differently by extrinsic currents. Finally, it is shown that by enhancing the differences in the responses of individual cells to a variety of stimuli, the interactions may facilitate a number of simple discriminations.     

Associative Training of Hermissenda

Reflex behavior of Hermissenda in response to visual and rotational stimuli is described. It is shown that repeated association of light with rotation modifies the subsequent responses of the animals to light. This modification does not occur after the same period of light or rotation alone. The effect of the associative training is strongly dependent on the amount of daily light with which the animals are maintained.     

Neural correlates of associative training in Hermissenda

Hair cells in Hermissenda respond to illumination of the ipsilateral and contralateral eyes. These responses are modified by associative training of the animal. The observed electrophysiological changes appear to result from changes in the photoreceptors' synaptic input to the hair cells.     

Emotional memory: selective enhancement by sleep

Never go to sleep on an argument: an old wives' tale or a scientifically proven technique for controlling the memories you store? Recent findings show that sleep selectively enhances emotional memories, creating a long-lasting and potentially traumatic representation of distressing experiences.     

Immunomodulation in patients receiving intravenous Bryostatin 1 in a phase I clinical study: comparison with effects of Bryostatin 1 on lymphocyte function in vitro

Summary Bryostatin 1 is a protein kinase C activator that inhibits growth of tumour cells and activates lymphocytes in vitro, properties that have encouraged its use in phase 1 clinical studies as an anticancer agent. We investigated interleukin-2(IL-2)-induced proliferation and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMC) from cancer patients receiving Bryostatin intravenously. After Bryostatin administration both LAK generation and proliferation were enhanced when patients' PBMC were stimulated with IL-2 in vitro. However, when normal donors' PBMC were cultured in vitro in the presence Bryostatin and IL-2, LAK induction was inhibited while IL-2-driven proliferation was increased. These effects were also seen following only 2 h exposure to Bryostatin and could be elicited by conditioned medium from Bryostatin-pretreated cells. Neither IL-4 nor interferon was detected in the conditioned medium. Bryostatin in vitro was found to increase expression of IL-2 receptors on CD4⁺, CD8⁺ and CD56⁺ cells and augment the proportion of CD8⁺ cells in conjunction with IL-2. We conclude that Bryostatin in combination with IL-2 in vitro enhances proliferation and IL-2 receptor expression on lymphocytes, favouring CD8⁺ cells while suppressing the generation of LAK activity. Intravenous administration of Bryostatin increases the potential of IL-2 to induce proliferation and LAK activity in lymphocytes which, taken together with its putative direct antitumour effect, makes Bryostatin an interesting candidate for clinical trials in combination with IL-2.B.F. and P.L.S. are supported by the Cancer Research Campaign     

Hair Cell Interactions in the Statocyst of Hermissenda

Hair cells in the statocyst of Hermissenda crassicornis respond to mechanical stimulation with a short latency (<2 ms) depolarizing generator potential that is followed by hyperpolarization and inhibition of spike activity. Mechanically evoked hyperpolarization and spike inhibition were abolished by cutting the static nerve, repetitive mechanical stimulation, tetrodotoxin (TTX), and Co⁺⁺. Since none of these procedures markedly altered the generator potential it was concluded that the hyperpolarization is an inhibitory synaptic potential and not a component of the mechanotransduction process. Intracellular recordings from pairs of hair cells in the same statocyst and in statocysts on opposite sides of the brain revealed that hair cells are connected by chemical and/or electrical synapses. All chemical interactions were inhibitory. Hyperpolarization and spike inhibition result from inhibitory interactions between hair cells in the same and in opposite statocysts.     

Potassium currents in presynaptic hair cells of Hermissenda.

Apart from their primary function as balance sensors, Hermissenda hair cells are presynaptic neurons involved in the Ca(2+)-dependent neuronal plasticity in postsynaptic B photoreceptors that accompanies classical conditioning. With a view to beginning to understand presynaptic mechanisms of plasticity in the vestibulo-visual system, a locus for conditioning-induced neuronal plasticity, outward currents that may govern the excitability of hair cells were recorded by means of a whole-cell patch-clamp technique. Three K+ currents were characterized: a 4-aminopyridine-sensitive transient outward K+ current (IA), a tetraethyl ammonium-sensitive delayed rectifier K+ current (IK,V), and a Ca(2+)-activated K+ current (IK,Ca). IA activates and decays rapidly; the steady-state activation and inactivation curves of the current reveal a window current close to the apparent resting voltage of the hair cells, suggesting that the current is partially activated at rest. By modulating firing frequency and perhaps damping membrane oscillations, IA may regulate synaptic release at baseline. In contrast, IK,V and IK,Ca have slow onset and exhibit little or no inactivation. These two K+ currents may determine the duration of the repolarization phase of hair-cell action potentials and hence synaptic release via Ca2+ influx through voltage-gated Ca2+ channels. In addition, IK,Ca may be responsible for the afterhyperpolarization of hair cell membrane voltage following prolonged stimulation.     

Associative learning in a network model of Hermissenda crassicornis

A time-varying Resistance-Capacitance (RC) circuit computer model was constructed based on known membrane and synaptic properties of the visualvestibular network of the marine snail Hermissenda crassicornis. Specific biophysical properties and synaptic connections of identified neurons are represented as lumped parameters (circuit elements) in the model; in the computer simulation, differential equations are approximated by difference equations. The model's output, membrane potential, an indirect measure of firing frequency, closely parallels the behavioral and electrophysiologic outputs of Hermissenda in response to the same input stimuli presented during and after associative learning. The parallelism of the computer modeled and the biologic outputs suggests that the model captures the features necessary and sufficient for associative learning.     

Associative learning in a network model of Hermissenda crassicornis

A companion paper in a previous issue of this journal presented a resistance-capacitance circuit computer model of the four-neuron visual-vestibular network of the invertebrate marine mollusk Hermissenda crassicornis. In the present paper, we demonstrate that changes in the model's output in response to simulated associative training is quantitatively similar to behavioral and electrophysiological changes in response to associative training of Hermissenda crassicornis. Specifically, the model demonstrates many characteristics of conditioning: sensitivity to stimulus contingency, stimulus specificity, extinction, and savings. The model's learning features also are shown to be devoid of non-associative components. Thus, this computational model is an excellent tool for examining the information flow and dynamics of biological associative learning and for uncovering insights concerning associative learning, memory, and recall that can be applied to the development of artificial neural networks.     

A dual synaptic effect on hair cells in Hermissenda

Type A photorecptors can produce an initial hyperpolarizing wave followed by a delayed long-lasting increase in firing which is usually accompanied by a small depolarizing wave. The initial hyperpolarizing wave arises from an increase in conductance while the depolarizing wave was shown to arise from a decrease in conductance. The data presented indicate that both effects produced by the type A photoreceptors in ipsilateral hair cells are synaptic.     

Dynamical aspects of in vitro conditioning in Hermissenda type B photoreceptor

Dynamics of changes in physiology and morphology were studied in Hermissenda photoreceptors after in vitro conditioning with paired light and vibration. An increase in input resistance of the type B photoreceptor was observed following 5 paired presentations of light and vibration. It peaked at 10 min after in vitro conditioning, then decreased to a level twice the pre-conditioning level for more than 60 min. Contraction of the terminal branches along centro-lateral direction was initiated 5 min after conditioning and reached its final state at 10 min after conditioning. The pairing specific contraction of the axon terminal was not observed in ASW containing anisomycin. The dynamics in physiology and morphology were completely parallel 30 min after conditioning. These findings suggested that in vitro conditioning induced contraction was dependent on protein synthesis dependent process initiated within 5 min after training trials and that the change of cell morphology is a form of short-term synaptic plasticity that involves changes in macromolecular synthesis. Present findings that functional remodeling at the terminal branch of the type B photoreceptor occurred within 10 min after conditioning was the fastest modification process reported so far.     

Time-Dependent Increase in Protein Phosphorylation Following One-Trial Enhancement in Hermissenda

Abstract: One-trial conditioning of the nudibranch mollusk Hermissenda produces short- and long-term changes in excitability (enhancement) of identified sensory neurons. To investigate the biochemical mechanisms underlying this example of plasticity, we have examined changes in protein phosphorylation at different times following the in vitro conditioning trial. Changes in the incorporation of ³²PO₄ into proteins were determined using two-dimensional polyacrylamide gel electrophoresis, autoradiography, and densitometry. Conditioning resulted in increases in levels of several phosphoproteins, five of which, ranging in apparent molecular mass from 22 to 55 kDa, were chosen for analysis. The increased phosphorylation of the 46- and 55-kDa phosphoproteins detected 2 h postconditioning was significantly greater than the level of phosphorylation detected in an unpaired control group, indicating that long-term enhancement is pairing specific. Statistically significant increases in phosphorylation as compared with the control group that received only light were detected immediately after conditioning (5 min) for the 55-, 46-, and 22-kDa phosphoproteins, at 1 h for the 55- and 46-kDa phosphoproteins, and at 2 h for the 55-, 46-, and 22-kDa phosphoproteins. The 46- and 55-kDa phosphoproteins are putative structural proteins, and the 22-kDa phosphoprotein is proposed to be a protein kinase C substrate previously identified in Hermissenda following multitrial classical conditioning. Time-dependent increases in protein phosphorylation may contribute to the induction and maintenance of different memory stages expressed in sensory neurons after one-trial conditioning.