Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Functional and motor neuronal analysis of defensive siphon responses in {\it Aplysia californica}

One of the central goals of neuroscience research is to determine how networks of neurons control and modify behavior. One of the most influential model systems for this kind of analysis is the siphon and gill withdrawal reflex of the marine mollusc A. californica. In response to tactile stimulation, the siphon displays 3 different responses: (1) a posterior pointing and leveling (flaring) of the siphon in response to tail stimulation (the siphon T response), (2) constriction and anterior pointing to head stimulation (the siphon H response) and (3) constriction and withdrawal between the animal's parapodia (the siphon S response). The siphon S response is pseudoconditioned by a noxious tail stimulus to resemble the siphon T response. Behavioral and combined behavioral/intracellular studies were conducted to determine the motor neuronal control of these behaviors and to search for mechanisms of siphon response transformation following pseudoconditioning. The present studies have found that the flaring component of pseudoconditioned siphon S responses occurs during mantle pumping (MP) triggered by noxious tail stimulation. Siphon stimulation also triggers MP, as recorded in neurons of the Interneuron II pattern generator which commands MP. The 4 LF$\rm\sb{SB}$ siphon motor neurons (SMNs) were found necessary and sufficient for the siphon T response, while SMNs RD$\rm\sb S$ and LD$\rm\sb{S1}$ were found necessary and sufficient for the siphon H response. Following pseudoconditioning, there is an increase in the number of evoked spikes to the test stimulus for the LF$\rm\sb{SB}$ cells and a decreased number for RD$\rm\sb S.$ Siphon flaring occurring during the pseudoconditioned response correlates with increased LF$\rm\sb{SB}$ activity during triggered MP cycles. This suggests that psuedoconditioning is in part due to reconfiguration of the motor outputs of the Interneuron II network. These results suggest that these defensive responses are controlled and patterned by a well-defined, finite set of motor neurons and interneurons (Interneuron II) that are dedicated to specific behavioral functions, but also have parallel distributed properties. ^

THE DECLINE OF ISCHEMIC HEART DISEASE MORTALITY IN TEXAS: HEALTH PLANNING IMPLICATIONS

This is a report on an empirical study of the decline of ischemic heart disease mortality in the State of Texas. The study period was from 1970 to 1977. The data was collected and analyzed at three different levels of analysis: state, health service area (HSA), and county. The study was designed to test five main hypotheses. They serve to test the role of the medical care system as a possible factor associated with the changing ischemic heart disease mortality trends.^ The principal findings of the study were that a reasonable relationship could be found between the number of emergency medical care personnel, the number of icu-ccu beds, the number of medical specialists and the percent of hospitals with icu-ccu and the decline in ischemic heart disease mortality for the State of Texas. However, non significant relationships were found between variables in the medical care system and ischemic heart disease mortality trends, at the health service area level of analysis. More specifically, the number of coronary care unit beds was found to be negatively correlated with the decline in ischemic heart disease mortality at the county level.^ While being limited in its scope, the study suggests that certain factors (emergency medical service, icu-ccu beds, percent of icu-ccu units, and medical specialists) have been shown to be associated with the observed decline in ischemic heart disease mortality. The study also suggests many avenues of future research that need to be explored. ^