AA/12-Lipoxygenase Signaling Contributes to Inhibitory Learning in Hermissenda Type B Photoreceptors

Conditioned inhibition (CI) is a major category of associative learning that occurs when an organism learns that one stimulus predicts the absence of another. In addition to being important in its own right, CI is interesting because its occurrence implies that the organism has formed an association between stimuli that are non-coincident. In contrast to other categories of associative learning that are dependent upon temporal contiguity (pairings) of stimuli, the neurobiology of CI is virtually unexplored. We have previously described a simple form of CI learning in Hermissenda, whereby animals’ phototactic behavior is increased by repeated exposures to explicitly unpaired (EU) presentations of light and rotation. EU conditioning also produces characteristic reductions in the excitability and light response, and increases several somatic K+ currents in Type B photoreceptors. Type B photoreceptors are a major site of plasticity for classical conditioning in Hermissenda. Because arachidonic acid (AA) and/or its metabolites open diverse K+ channels in many cell types, we examined the potential contribution of AA to CI. Our results indicate that AA contributes to one of the major effects of EU-conditioning on Type B photoreceptors: decreases in light-evoked spike activity. We find that AA increases the transient (IA) somatic K+ current in Type B photoreceptors, further mimicking CI training. In addition, our results indicate that metabolism of AA by a 12-lipoxygenase enzyme is critical for these effects of AA, and further that 12-lipoxygenase metabolites are apparently generated during CI training

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory.

Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage

Historical review of research on protein kinase C in learning and memory

1. In 1977, the discovery of a new type of kinase was reported, which turned out to be a receptor for phorbol esters. Thereafter, several mechanisms regulating PKC activity and various PKC subtypes have been discovered. 2. A role for PKC in synaptic plasticity and information storage has been postulated in the mid-1980s. An important role for PKC has since been suggested in several learning and memory models, in which persistent changes in the activation of PKC outlasting the initial stimulating event are thought to be crucial. 3. A vast number of experiments have further substantiated a role of PKC in learning and memory using molecular genetic, behavioral, pharmacological, electrophysiological or immunocytochemical approaches in the late 1980s and the 1990s. PKC research of the past decade or so of has shown some exciting aspects of the putative role of PKC in synaptic plasticity and information storage. 4. The authors have provided highlights (Table 1) on research on PKC

Investigating Serotonin Receptor Expression in Single Homologous Neurons Underlying Independently Evolved and Species-Specific Behaviors

Serotonin (5-HT) receptors modulate neuronal and synaptic properties, altering the functional output of neural circuits. Changing the functions of a neural circuit can alter behavior. Over evolutionary time, species differences in neuromodulation could allow for species-specific behaviors to evolve. To investigate this idea, this dissertation compared neuromodulatory receptor gene expression underlying species-specific swimming behaviors in sea slugs. The sea slug Tritonia diomedea (Mollusca, Gastropoda, Nudipleura, Nudibranchia), performs a rhythmic dorsal-ventral (DV) escape swim behavior. The behavior is controlled by a central pattern generator (CPG), composed of a small number of large, identifiable neurons. During swimming, 5-HT enhances the synaptic strength of a neuron in the swim CPG, called C2. In contrast, the nudibranch Hermissenda crassicornis does not swim in this manner. It has C2 homologues, and 5-HT is present, however, 5-HT does not modulate C2 synaptic strength. Pleurobranchaea californica, a Nudipleura species belonging to a sister clade of Nudibranchia, swims with DV flexions, although in this species swimming varies within individuals. 5-HT enhances Pleurobranchaea C2 homologue synaptic strength in swimming animals, only. Phylogenetic analysis showed that Tritonia and Pleurobranchaea independently evolved DV-swimming. Thus, there is a correlation between independently evolved swimming and serotonergic modulation of C2 homologues. It was hypothesized that 5-HT receptor differences in C2 neurons underlie species-specific swimming and modulation. To test this hypothesis, 5-HT receptor genes were identified in each species. A total of seven receptor subtypes, from five gene families, were found to be expressed in the brains of each species. Using single-cell quantitative PCR (qPCR), 5-HT receptor expression profiles were determined in C2 homologues. Genes known as 5-HT2a and 5-HT7 were expressed in C2 homologues from Tritonia and swimming Pleurobranchaea, only. Single-neuron transcriptome sequencing verified these results. The expression profiles of neuromodulatory receptor genes in single, homologous neurons correlated with species-specific swimming and modulation. The results illustrate how differences in neuromodulatory gene expression may alter the functional output of homologous neural structures, shedding light on a means by which neuromodulation can alter the brain to facilitate the evolution of species-specific behaviors. Evolution, Mollusc, Neuromodulation, Serotonin, Receptor, Behavior, Next-Generation Sequencing, Transcriptomic

Metabotropic Glutamate Receptor Activation in Cerebelar Purkinje Cells as Substrate for Adaptive Timing of the Classicaly Conditioned Eye Blink Response

To understand how the cerebellum adaptively times the classically conditioned nictitating membrane response (NMR), a model of the metabotropic glutamate receptor (mGluR) second messenger system in cerebellar Purkinje cells is constructed. In the model slow responses, generated postsynaptically by mGluR-mediated phosphoinositide hydrolysis, and calcium release from intracellular stores, bridge the interstimulus interval (ISI) between the onset of parallel fiber activity associated with the conditioned stimulus (CS) and climbing fiber activity associated with unconditioned stimulus (US) onset. Temporal correlation of metabotropic responses and climbing fiber signals produces persistent phosphorylation of both AMPA receptors and Ca2+-dependent K+ channels. This is responsible for long-term depression (LTD) of AMPA receptors. The phosphorylation of Ca2+-dependent K+ channels leads to a reduction in baseline membrane potential and a reduction of Purkinje cell population firing during the CS-US interval. The Purkinje cell firing decrease disinhibits cerebellar nuclear cells which then produce an excitatory response corresponding to the learned movement. Purkinje cell learning times the response, while nuclear cell learning can calibrate it. The model reproduces key features of the conditioned rabbit NMR: Purkinje cell population response is properly timed, delay conditioning occurs for ISIs of up to four seconds while trace conditioning occurs only at shorter ISIs, mixed training at two different ISis produces a double-peaked response, and ISIs of 200-400ms produce maximal responding. Biochemical similarities between timed cerebellar learning and photoreceptor transduction, and circuit similarities between the timed cerebellar circuit and a timed dentate-CA3 hippocampal circuit, are noted.Office of Naval Research (N00014- 92-J-4015, N00014-92-J-1309, N00014-95-1-0409); Air Force Office of Scientific Research (F49620-92-J-0225);National Science Foundation (IRI-90-24877

Functional Changes in the Snail Statocyst System Elicited by Microgravity

BACKGROUND: The mollusk statocyst is a mechanosensing organ detecting the animal's orientation with respect to gravity. This system has clear similarities to its vertebrate counterparts: a weight-lending mass, an epithelial layer containing small supporting cells and the large sensory hair cells, and an output eliciting compensatory body reflexes to perturbations. METHODOLOGY/PRINCIPAL FINDINGS: In terrestrial gastropod snail we studied the impact of 16- (Foton M-2) and 12-day (Foton M-3) exposure to microgravity in unmanned orbital missions on: (i) the whole animal behavior (Helix lucorum L.), (ii) the statoreceptor responses to tilt in an isolated neural preparation (Helix lucorum L.), and (iii) the differential expression of the Helix pedal peptide (HPep) and the tetrapeptide FMRFamide genes in neural structures (Helix aspersa L.). Experiments were performed 13-42 hours after return to Earth. Latency of body re-orientation to sudden 90° head-down pitch was significantly reduced in postflight snails indicating an enhanced negative gravitaxis response. Statoreceptor responses to tilt in postflight snails were independent of motion direction, in contrast to a directional preference observed in control animals. Positive relation between tilt velocity and firing rate was observed in both control and postflight snails, but the response magnitude was significantly larger in postflight snails indicating an enhanced sensitivity to acceleration. A significant increase in mRNA expression of the gene encoding HPep, a peptide linked to ciliary beating, in statoreceptors was observed in postflight snails; no differential expression of the gene encoding FMRFamide, a possible neurotransmission modulator, was observed. CONCLUSIONS/SIGNIFICANCE: Upregulation of statocyst function in snails following microgravity exposure parallels that observed in vertebrates suggesting fundamental principles underlie gravi-sensing and the organism's ability to adapt to gravity changes. This simple animal model offers the possibility to describe general subcellular mechanisms of nervous system's response to conditions on Earth and in space

The 1986-87 NASA space/gravitational biology accomplishments

This report consists of individual technical summaries of research projects of NASA's Space/Gravitational Biology program, for research conducted during the period January 1986 to April 1987. This program utilizes the unique characteristics of the space environment, particularly microgravity, as a tool to advance knowledge in the biological sciences; understanding how gravity has shaped and affected life on Earth; and understanding how the space environment affects both plant and animal species. The summaries for each project include a description of the research, a list of accomplishments, an explanation of the significance of the accomplishments, and a list of publications