Thomas W. Abrams

Habituation revisited: an updated and revised description of the behavioral characteristics of habituation.

The most commonly cited descriptions of the behavioral characteristics of habituation come from two papers published almost 40 years ago [Groves, P. M., & Thompson, R. F. (1970). Habituation: A dual-process theory. Psychological Review, 77, 419-450; Thompson, R. F., & Spencer, W. A. (1966). Habituation: A model phenomenon for the study of neuronal substrates of behavior. Psychological Review, 73, 16-43]. In August 2007, the authors of this review, who study habituation in a wide range of species and paradigms, met to discuss their work on habituation and to revisit and refine the characteristics of habituation. This review offers a re-evaluation of the characteristics of habituation in light of these discussions. We made substantial changes to only a few of the characteristics, usually to add new information and expand upon the description rather than to substantially alter the original point. One additional characteristic, relating to long-term habituation, was added. This article thus provides a modern summary of the characteristics defining habituation, and can serve as a convenient primer for those whose research involves stimulus repetition.

Protein kinase C acts as a molecular detector of firing patterns to mediate sensory gating in Aplysia

Habituation of a behavioral response to a repetitive stimulus enables animals to ignore irrelevant stimuli and focus on behaviorally important events. In Aplysia, habituation is mediated by rapid depression of sensory synapses, which could leave an animal unresponsive to important repetitive stimuli, making it vulnerable to injury. We identified a form of plasticity that prevents synaptic depression depending on the precise stimulus strength. Burst-dependent protection from depression is initiated by trains of 2–4 action potentials and is distinct from previously described forms of synaptic enhancement. The blockade of depression is mediated by presynaptic Ca2+ influx and protein kinase C (PKC) and requires localization of PKC via a PDZ domain interaction with Aplysia PICK1. During protection from depression, PKC acts as a highly sensitive detector of the precise pattern of sensory neuron firing. Behaviorally, burst-dependent protection reduces habituation, enabling animals to maintain responsiveness to stimuli that are functionally important.

Evolutionary Conservation of the Signaling Proteins Upstream of Cyclic AMP-Dependent Kinase and Protein Kinase C in Gastropod Mollusks

The protein kinase C (PKC) and the cAMP-dependent kinase (protein kinase A; PKA) pathways are known to play important roles in behavioral plasticity and learning in the nervous systems of a wide variety of species across phyla. We briefly review the members of the PKC and PKA family and focus on the evolution of the immediate upstream activators of PKC and PKA i.e., phospholipase C (PLC) and adenylyl cyclase (AC), and their conservation in gastropod mollusks, taking advantage of the recent assembly of the Aplysiacalifornica and Lottia gigantea genomes. The diversity of PLC and AC family members present in mollusks suggests a multitude of possible mechanisms to activate PKA and PKC; we briefly discuss the relevance of these pathways to the known physiological activation of these kinases in Aplysia neurons during plasticity and learning. These multiple mechanisms of activation provide the gastropod nervous system with tremendous flexibility for implementing neuromodulatory responses to both neuronal activity and extracellular signals.

Persistence of the Interaction of Calmodulin with Adenylyl Cyclase: Implications for Integration of Transient Calcium Stimuli

Abstract: Ca2+/calmodulin‐sensitive adenylyl cyclase plays a role in several forms of synaptic plasticity and learning. To understand how cellular signals from neuronal activity during behavioral stimuli might be integrated by adenylyl cyclase, we have characterized the response of type I adenylyl cyclase to transient Ca2+ stimuli. Stimulation by a several second Ca2+ stimulus is delayed, rising to a peak after the Ca2+ stimulus has ended. We attempted to identify the site of the persistent Ca2+ signal that enabled adenylyl cyclase stimulation to increase after free Ca2+ had declined. Free calmodulin itself displayed no persistent activation by Ca2+ and was unable to activate adenylyl cyclase if exposed to low Ca2+ solution <1 s before reaching adenylyl cyclase. In contrast, activation of the calmodulin‐adenylyl cyclase complex persisted for seconds after Ca2+ stimulus. Activation decayed with a time constant of 6 or 13 s depending on assay conditions. These results suggest that the calmodulin‐adenylyl cyclase complex can serve as a site of cellular memory for a Ca2+ transient that has ended even before adenylyl cyclase is fully activated.

Serotonin stimulation of cAMP-dependent plasticity in Aplysia sensory neurons is mediated by calmodulin-sensitive adenylyl cyclase

Calmodulin (CaM)-sensitive adenylyl cyclase (AC) in sensory neurons (SNs) in Aplysia has been proposed as a molecular coincidence detector during conditioning. We identified four putative ACs in Aplysia CNS. CaM binds to a sequence in the C1b region of AC-AplA that resembles the CaM-binding sequence in the C1b region of AC1 in mammals. Recombinant AC-AplA was stimulated by Ca2+/CaM. AC-AplC is most similar to the Ca2+-inhibited AC5 and AC6 in mammals. Recombinant AC-AplC was directly inhibited by Ca2+, independent of CaM. AC-AplA and AC-AplC are expressed in SNs, whereas AC-AplB and AC-AplD are not. Knockdown of AC-AplA demonstrated that serotonin stimulation of cAMP-dependent plasticity in SNs is predominantly mediated by this CaM-sensitive AC. We propose that the coexpression of a Ca2+-inhibited AC in SNs, together with a Ca2+/CaM-stimulated AC, would enhance the associative requirement for coincident Ca2+ influx and serotonin for effective stimulation of cAMP levels and initiation of plasticity mediated by AC-AplA.

Studies on Aplysia neurons suggest treatments for chronic human disorders

For decades, the marine snail Aplysia has proven to be a powerful system for analyzing basic neurobiological mechanisms, particularly cellular and molecular mechanisms of neural plasticity. Three new findings on Aplysia may be relevant for the understanding and treatment of chronic human disorders. This research on this simple molluscan nervous system may lead to new therapeutic approaches for spinal cord injury, Fragile X syndrome, and genetic learning deficits more generally.

Sequence-dependent interactions between transient calcium and transmitter stimuli in activation of mammalian brain adenylyl cyclase

Recent evidence implicates Ca2+/CaM-sensitive adenylyl cyclase (AC) as a molecular coincidence detector for temporally paired stimuli during associative learning. During conditioning in Aplysia, AC is optimally activated when Ca2+ influx, the cellular signal for the conditioned stimulus (CS), precedes binding of modulatory transmitter, the cellular signal for the unconditioned stimulus (US). This sequence preference of the AC for Ca2+-before-transmitter, parallels the CS-preceding-US pairing requirement of classical conditioning. In this study, we have examined the response of AC from rat cerebellum to brief exposures to Ca2+ and to transmitter in a perfused membrane assay. We observed modest synergism between Ca2+ and transmitter in activating AC. Activation was more effective when a Ca2+ stimulus immediately preceded a transmitter stimulus than when the two stimuli were delivered in the reverse order. Thus, rat cerebellar AC displayed a sequence preference for optimal activation by paired stimuli similar to that observed in Aplysia; this sequence dependence could contribute to the CS-US sequence requirement observed in most mammalian classical conditioning paradigms.

Trans-Synaptic Plasticity: Presynaptic Initiation, Postsynaptic Memory

A novel mechanism of persistent facilitation induced by serotonin at Aplysia synapses depends upon rapid postsynaptic protein synthesis and increased responsiveness to glutamate; whereas the memory for this synaptic change is postsynaptic, the initiating signal may be an increase in spontaneous release of glutamate from the presynaptic terminals.

Novel approach for generation of low calcium reagents for investigations of heavy metal effects on calcium signaling

INTRODUCTION Lead exposure can cause learning disabilities, memory loss and severe damage to the nervous system. However, the exact mechanism by which lead causes learning disabilities is not fully understood. The effects of lead on calcium-regulated signaling pathways are difficult to study biochemically; with the traditional method of controlling the free calcium concentration with EGTA, the exact concentrations of free lead and calcium ions in solution are interdependent and prone to error because EGTA also buffers lead. METHODS AND RESULTS In our approach, we first reduced the free calcium concentration in the solution using calcium-binding resins before adding lead to buffers. The solution was sequentially treated with Chelex-100 ion exchange resin, followed by immobilized BAPTA resin. The final concentration of free calcium in the solution was measured with Fluo-3 indicator. Our protocol successfully produced buffers with free calcium levels below 15 nM, which is substantially below threshold for activation of calcium-dependent enzymes in signaling pathways (which is typically a few hundred nanomolar calcium, when determined in vitro). CONCLUSION This method provides an improved approach to study the effect of heavy metals on calcium-stimulated signaling pathways.

Synaptic Plasticity: Cleaved Kinases and the Specificity of Erasing Traumatic Memories

New possibilities for treating posttraumatic stress disorder and anxiety disorders involving abnormal memories are emerging from analysis of persistent protein kinase activation and mechanisms of synapse-specific modification, known as synaptic tagging.