An investigation of the neural mechanisms of interval timing behaviour

Timing behaviour plays an important role in the daily living of individuals from a great variety of species. For example, organisms must be able to discriminate between the durations of relevant events (temporal discrimination) and to regulate their own behaviour in time (temporal differentiation). The processes that allow animals to adjust their behaviour to the temporal regularities of the environment have been studied using different procedures which model the relationship between time and behaviour. A taxonomy of timing based on the subject’s location in time with respect to the signalled duration has been proposed. When an organism judges the duration of an elapsed interval the timing is retrospective (e.g. interval bisection); when it responds during an elapsing duration the timing is immediate (e.g. fixed-interval peak procedure); and finally when it chooses between future delayed outcomes the timing is prospective (e.g. inter-temporal choice schedules). It has been proposed that the cortico-striato-thalamo-cortical (CSTC) circuits play a special role in interval timing and inter-temporal choice behaviour. This thesis examined whether performance of timing tasks by rats induces neuronal activation within the prefrontal cortex and corpus striatum, as revealed by Fos expression, and explored a new approach to analyzing performance in an inter-temporal choice schedule. Chapter 1 describes the literature which forms the background of the project. It reviews interval timing and inter-temporal choice methodology and theory, the neurobiological substrates underlying both kinds of behaviour, and finally Fos expression, as a marker of neuronal activation. Chapters 2-4 present experiments that examined whether, in intact rats, performance of different interval timing tasks was associated with neuronal activation in the dorsal striatum and prefrontal cortex, as revealed by expression of the Fos protein, the product of the immediate-early gene c-fos (Experiments 1-3). Chapters 5-7 present experiments focused on some behavioural and neurobiological aspects of inter-temporal choice behaviour. One purpose of these experiments was to develop an abbreviated approach to estimate the rate of delay discounting (K) and reinforcer size sensitivity parameter (Q) based on the Multiplicative Hyperbolic Model of inter-temporal choice (MHM), using the adjusting-delay schedule. Additionally a novel way of quantifying transitional behaviour in the adjusting-delay schedule was presented based on analysis of the power spectrum of cyclical changes in the adjusting delay, dB (Experiment 4). This approach was used to analyze data obtained from rats performing on the adjusting-delay schedule under methodological manipulations (Experiment 5) and neurobiological interventions (Experiment 6). Experiment 1 (Chapter 2) investigated whether, in intact rats, performance on the discrete-trials temporal discrimination task was associated with neuronal activation in the prefrontal cortex and corpus striatum, as revealed by enhanced Fos expression in these areas. Performance on temporal and light-intensity discrimination tasks was well described by a two-parameter logistic equation. The rats trained under the timing task showed increased Fos expression in the orbital prefrontal cortex (OPFC) and the nucleus accumbens (Acb) compared to the rats trained under the light-intensity discrimination task, indicating a substantial activation of these areas during the timing task. However, there was no evidence for involvement of the dorsal striatum in the performance of this task. Experiment 2 (Chapter 3) examined whether performance on an interval-bisection task in the range of milliseconds showed increased Fos expression in the prefrontal cortex and corpus striatum compared to performance under a light-intensity bisection task. Performance on both bisection tasks conformed to the conventional logistic psychometric function. The rats trained under the timing task showed increased Fos expression in the OPFC, infralimbic and prelimbic cortex and Acb compared to the rats trained under the light-intensity bisection task. The results provided no evidence for an involvement of the dorsal striatum in the performance of this task. Experiment 3 (Chapter 4) investigated whether performance on the fixed-interval peak procedure (FIPP) was associated with increased neuronal activity in the prefrontal cortex and corpus striatum, as revealed by Fos expression. The results showed that response rate during peak trials was characterized by a ‘Gaussian plus ramp’ function, with maximal responding (peak rate) occurring around the time of the reinforcement in the FI trials (peak time). Consistent with the results of Experiments 1 and 2, the concentration of Fos-positive neurones in the OPFC was greater in rats exposed to FIPP than in rats exposed to a VI schedule. However, the results did not provide any evidence for a specific involvement of the dorsal or ventral striatum in FIPP performance. In Experiment 4 (Chapter 5), rats made repeated choices on an adjusting-delay schedule. Indifference delays, calculated from adjusting delays in the last 10 sessions, were shorter when the sizes of reinforcers were 14 and 25 µl of a 0.6 M sucrose solution than when they were 25 and 100 µl of the same solution. The ratio of the indifference delays (d50) was significantly smaller than that predicted on the basis of an assumed linear relation between reinforcer size and instantaneous reinforcer value. Estimates of K and Q fell within the values reported previously. Adjusting delays in successive blocks of trials were analysed using the Fourier transform. The power spectra obtained from individual rats had a dominant frequency that corresponded to a period of oscillation of the adjusting delay between 30 and 100 trial blocks. Power in the dominant frequency band declined with extended training. Experiment 5 (Chapter 6) examined the pattern of oscillation of dB in an adjusting-delay schedule using the power spectrum analysis. The step-size in which the delay to the larger reinforcer (dB) increased or decreased was tested across two conditions. In Condition 1, dB increased or decreased (according to the rats’ choice) by 20% from block n to block n+1. In Condition 2, the step size was 10%. The power spectrum analysis showed that the period of oscillation of the dominant frequency of the spectrum was significantly longer under Condition 2 than under Condition 1. There was a consistent trend for the power of oscillation to be higher in the initial segment of the experiment in both conditions. Experiment 6 (Chapter 7) examined the effect of excitotoxic lesion of the core of the nucleus accumbens (AcbC) on K and Q in an adjusting delay schedule using the same protocol as Experiment 4. The effect of the lesion on the power spectrum parameters was also examined. The AcbC-lesioned group showed significantly lower values of d50 than the sham-lesioned group. The ratio of the indifference delays seen in both groups was substantially less than the value predicted on the basis of an assumed linear relation between reinforcer size and instantaneous reinforcer value. K was higher in the lesioned group than in the sham-lesioned group; Q was not affected by the AcbC lesion. Neither the spectral power within the dominant frequency band nor the period corresponding to the dominant frequency differed significantly between groups. The final chapter (Chapter 8) summarizes the findings of the experiments, and discusses their implications for the putative role of the prefrontal cortex, and ventral and dorsal striatum in interval timing and inter-temporal choice, and for theoretical models of these behaviours. The role of the dorsal striatum is questioned, while a possible role of the Acb in temporal processing is proposed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo