Abstract
Repeated noxious stimulation produces long-term sensitization of defensive withdrawal reflexes in Aplysia californica, a form of long-term memory that requires changes in both transcription and translation. Previous work has identified 10 transcripts which are rapidly up-regulated after long-term sensitization training in the pleural ganglia. Here we use quantitative PCR to begin examining how these transcriptional changes are expressed in different CNS loci related to defensive withdrawal reflexes at 1 and 24 hours after long-term sensitization training. Specifically, we sample from a) the sensory wedge of the pleural ganglia, which exclusively contains the VC nociceptor cell bodies that help mediate input to defensive withdrawal circuits, b) the remaining pleural ganglia, which contain withdrawal interneurons, and c) the pedal ganglia, which contain many motor neurons. Results from the VC cluster show different temporal patterns of regulation: 1) rapid but transient up-regulation of Aplysia homologs of C/EBP, C/EBPγ, and CREB1, 2) delayed but sustained up-regulation of BiP, Tolloid/BMP-1, and sensorin, 3) rapid and sustained up-regulation of Egr, GlyT2, VPS36, and an uncharacterized protein (LOC101862095), and 4) an unexpected lack of regulation of Aplysia homologs of calmodulin (CaM) and reductase-related protein (RRP). Changes in the remaining pleural ganglia mirror those found in the VC cluster at 1 hour but with an attenuated level of regulation. Because these samples had almost no expression of the VC-specific transcript sensorin, our data suggests that sensitization training likely induces transcriptional changes in either defensive withdrawal interneurons or neurons unrelated to defensive withdrawal. In the pedal ganglia, we observed only a rapid but transient increase in Egr expression, indicating that long-term sensitization training is likely to induce transcriptional changes in motor neurons but raising the possibility of different transcriptional endpoints in this cell type.
Highlights
How are long-term memories maintained despite molecular turnover in the central nervous system? The answer to this question seems to depend, in part, on learning-induced changes in gene expression
For animals in the 24-hour condition (n512), we measured the efficacy of training via the tail-elicited siphon-withdrawal response (T-siphon-withdrawal reflex (SWR)), a test site not included in training and representing generalized sensitization
As expected, training produced a robust increase in tail-elicited siphonwithdrawal reflex (T-SWR) duration on the side of training but no change in reflex duration on the untrained side (Fig. 2)
Summary
How are long-term memories maintained despite molecular turnover in the central nervous system? The answer to this question seems to depend, in part, on learning-induced changes in gene expression. In a wide range of species and learning paradigms, training that produces long-term memory evokes changes in neuronal gene expression [1,2,3]. Blocking changes in gene expression has been repeatedly shown to impair the formation of long-term memory [4,5,6,7,8]. Sensitization in the marine mollusk Aplysia californica has proven a fruitful paradigm for studying the transcriptional mechanisms of long-term memory ( Fig. 1A). Sensitization is an increase in reflex responsiveness due to noxious stimulation [9]. This non-associative form of memory is observed across the entire animal kingdom [10]. Sensitization in Aplysia shares many behavioral, physiological, and molecular characteristics with aspects of chronic pain in humans and other mammals [12, 13], and research in Aplysia has proven informative for helping to guide research into this important clinical problem [14]
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