LEARNING IMPULSE CONTROL IN A NOVEL ANIMAL MODEL: SYNAPTIC, CELLULAR, AND PHARMACOLOGICAL SUBSTRATES

Impulse control, an executive process that restrains inappropriate actions, is impaired in numerous psychiatric conditions. This thesis reports three experiments that utilized a novel animal model of impulse control, the response inhibition (RI) task, to examine the substrates that underlie learning this task. In the first experiment, rats were trained to withhold responding on the RI task, and then euthanized for electrophysiological testing. Training in the RI task increased the AMPA/NMDA ratio at the synapses of pyramidal neurons in the prelimbic, but not infralimbic, region of the medial prefrontal cortex. This enhancement paralleled performance as subjects underwent acquisition and extinction of the inhibitory response. AMPA/NMDA was elevated only in neurons that project to the ventral striatum. Thus, this experiment identified a synaptic correlate of impulse control. In the second experiment, a separate group of rats were trained in the RI task prior to electrophysiological testing. Training in the RI task produced a decrease in membrane excitability in prelimbic, but not infralimbic, neurons as measured by maximal spiking evoked in response to increasing current injection. Importantly, this decrease was strongly correlated with successful inhibition in the task. Fortuitously, subjects trained in an operant control condition showed elevated infralimbic, but not prelimbic, excitability, which was produced by learning an anticipatory signal that predicted imminent reward availability. These experiments revealed two cellular correlates of performance, corresponding to learning two different associations under distinct task conditions. In the final experiment, rats were trained on the RI task under three conditions: Short (4-s), long (60-s), or unpredictable (1-s to 60-s) premature phases. These conditions produced distinct errors on the RI task. Interestingly, amphetamine increased premature responding in the short and long conditions, but decreased premature responding in the unpredictable condition. This dissociation may arise from interactions between amphetamine and underlying cognitive processes, such as attention, timing, and conditioned avoidance. In summary, this thesis showed that learning to inhibit a response produces distinct synaptic, cellular, and pharmacological changes. It is hoped that these advances will provide a starting point for future therapeutic interventions of disorders of impulse control.

Using the interact system model to analyze computer mediated communication during a small group problem-solving task

The Interact System Model (ISM) developed by Fisher and Hawes (1971) for the analysis of face-to-face communication during small-group problem solving activities was used to study online communication. This tool proved to be of value in the analysis, but the conversation patterns reported by Fisher (1980) did not fully appear in the online environment. Participants displayed a habit of "being too polite" and not fully voicing their disagreements with ideas posed by others. Thus progress towards task completion was slow and incomplete.

The role of Schizosaccharomyces pombe Cdc2 phosphorylation sites on Cdc25 in mitotic timing

Cell size control and mitotic timing in Schizosaccharomyces pombe is coupled to the environment through several signal transduction pathways that include stress response, checkpoint and nutritional status impinging on Cdc25 tyrosine phosphatase and Wee1 tyrosine kinase. These in turn regulate Cdc2 (Cdk1) activity and through a double feedback loop, further activates Cdc25 on 12 possible phosphorylation sites as well as inhibiting Wee1. Phosphomutants of the T89 Cdc2 phosphorylation site on Cdc25, one with a glutamate substitution (T89E) which is known to phosphomimetically activate proteins and an alanine substitution (T89A), which is known to block phosphorylation, exhibit a small steady-state cell size (semi-wee phenotype), a known hallmark for aberrant mitotic control. To determine whether the T89 phosphorylation site plays an integral role in mitotic timing, the phosphomutants were subjected to nitrogen shifts to analyze their transient response in the context of nutritional control. Results for both up and downshifts were replicated for the T89E phosphomutant, however, for the T89A phosphomutant, only a nutritional downshift has been completed so far. We found that the steady-state cell size of both phosphomutants was significantly smaller than the wild-type and in the context of nutritional control. Furthermore, the constitutively activated T89E phosphomutant exhibits residual mitotic entry, whereas the wild-type undergoes a complete mitotic suppression with mitotic recovery also occurring earlier than the wild-type. In response to downshifts, both phosphomutants exhibited an identical response to the wild-type. Further characterization of the other Cdc2 phosphorylation sites on Cdc25 are required before conclusions can be drawn, however T89 remains a strong candidate for being important in activating Cdc25.