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• W2159002183 abstract "According to contemporary learning theory, instrumental actions are controlled, in a large part, by two dissociable systems. Whilst goal-directed actions are driven by an explicit awareness of an anticipated outcome, habitual responses are the product of previously reinforced associations between contextual stimuli and salient outcomes.Although experimental lesion studies and pathological disorders, such as drug addiction and Parkinson's disease, have advanced our knowledge of the brain circuitriesimportant in the regulation of instrumental behaviour, we still do not have a full understanding of the executive mechanisms regulating the expression of these behavioursor the neural processes which underlie the shift from �exible goal-directed actions to stimulus-bound habits that occurs naturally following repeated practice.The present work focused speci�cally on the molecular mechanisms involved in this shift. The �rst experimental section, Chapter 3, established a protocol for modellinggoal-directed and habitual instrumental responding in rats. Experiment 1 measured the sensitivity of lever press responding to changes in outcome value, as an indexof goal-directed behaviour, in groups of rats sourced from either Charles River or Harlan. After three sessions of instrumental training, only rats sourced from CharlesRiver and devalued in the same context that they were trained in, rather than in a di�erent context, reduced responding for a devalued outcome. Building on these�ndings, in Experiment 2 a separate group of rats, sourced from Charles River, was trained to level press over 10 sessions. In contrast to the �rst experiment, lever pressresponding at test in this group of animals was insensitive to outcome devaluation.These initial experiments demonstrated evidence consistent with a training-induced shift from goal-directed to habitual instrumental behaviour and were used to inform the design of a second set of experiments, described in Chapter 4, in which region-speci�c di�erences in gene expression were compared across groups of rats with di�erent levels of lever press experience. DNA microarray analysis of tissue samples from the dorsolateral (DLS) and posterior dorsomedial striatum (pDMS), using Rat Gene 2.0 ST A�ymetrix arrays, revealed both training group- and brain region-speci�c ef-fects. Evidence of a high proportion of non-linear regulation pro�les across the training groups was indicative of experience-dependent shifts in gene expression; further-more, the high degree of separation between the training-dependent expression pro�les of the DLS and pDMS points to the dynamic engagement of distinct, region-speci�c regulatory networks over the course of instrumental learning.The experiments presented in Chapter 5 went on to investigate the role of epigenetic mechanisms, speci�cally histone acetylation, in the regulation of instrumentalbehaviour by using the histone deacetylase inhibitor sodium butyrate (NaB) to interfere with endogenous chromatin remodelling processes. The e�ects of systemic injections of NaB on the sensitivity of lever press behaviour to changes in outcome value were assessed in three separate studies, each designed to target a di�erent stage of learning. NaB had no e�ect on the acquisition or consolidation of goal-directedbehaviour. However, after three sessions of training, the instrumental behaviour of animals receiving an injection of NaB prior to exticntion test was less sensitive toreinforcer devaluation relative to controls, suggesting that histone acetylation may be involved in the retrieval phase of instrumental learning.In an attempt to address some of the limitations of systemic drug administration, the �nal experimental chapter, Chapter 6, describes an initial exploratory investigationinto the e�ects of administering NaB directly into the brain using a microinfusion protocol. Western blot analysis showed an increase in histone H4 acetylation in the mPFC following infusions of NaB targeting the infralimbic cortex. Behavioural data suggested that NaB may act to ameliorate some of the damaging e�ects of the infusion procedure, with NaB-treated animals showing enhanced sensitivity tooutcome devaluation relative to controls. These preliminary data act as proof of principle for the development of a microinfusion protocol for studying the role of histone acetylation in instrumental learning and highlight a number of practical issues which will be addressed in ongoing work.Taken together the experiments presented in this thesis provide evidence for the existence of discrete gene expression changes associated with minimal or extended training regimes, and for highly speci�c e�ects of a systemically administered HDACi on components of instrumental behaviour. These data o�er new insights into the molecular mechanisms involved in the regulation of instrumental learning in rodents and provide a starting point for further investigations into the role that epigenetic processes may play in the neural plasticity underlying the transition from goal-directed to habitual behaviour" @default.
• W2159002183 created "2016-06-24" @default.
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• W2159002183 date "2013-01-01" @default.
• W2159002183 modified "2023-09-24" @default.
• W2159002183 title "Investigating the molecular substrates of goal-directed and habitual behaviour" @default.
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