Attention in Rodents: Pharmacology and the Role of the Frontoparietal Network

Abstract

The recent high profile Phase III failures of new drugs to treat psychiatric disorders demonstrated that there is a clear need to improve translation of pre-clinical findings. The Research Domain Criteria (RDoC) proposes that this can be achieved by focusing on trans-diagnostic criteria. A good example of this is inattention, which is prevalent in conditions such as schizophrenia, Alzheimer's disease and attention deficit hyperactivity disorder (ADHD). Validating and refining novel and existing models of inattention will facilitate development of new therapeutic strategies. The work presented in thesis refines a rat model of low attention to increase its translational potential for investigating attention promoting compounds. RDoC also suggests that research at multiple levels of analysis is essential. Therefore, this work also investigates involvement of the frontoparietal network in attention using electrophysiology and c-Fos techniques ex vivo. This thesis first refines a 5 choice-continuous performance task (5C-CPT) method to group rats based on attentional performance by using a more translational calculation of vigilance (d prime) alongside stricter separation criteria. This method demonstrated pharmacological validity by replicating previous effects of methylphenidate and atomoxetine in low attentive (LA) rats. It also showed enhanced translational potential by revealing reduced omissions (increased sustained attention) in LA rats, which is an important clinical symptom that the previous method failed to uncover. Nicotine and caffeine, which improve sustained attention in humans, were assessed in high and low attentive animals. Both compounds increased impulsivity (probability of false alarms (pFA)), irrespective of attentive grouping. However, these impulsive symptoms may have been caused by off-target effects. This was controlled for by testing the selective alpha 7 nicotinic acetylcholine receptor partial agonist encenicline. The rationale for this was that knockout of the alpha 7 nicotinic acetylcholine receptor promotes an inattentive phenotype in mice; therefore, encenicline was studied for its potential to improve attention. Encenicline improved accuracy, d prime and pFA, in LA rats, showing the potential of this target to improve attention, vigilance and impulsivity, respectively. Therefore, it is proposed that partial agonists at the alpha 7 nicotinic acetylcholine receptor warrant further investigation for inattention symptoms. Connections between the prefrontal cortex (PFC) and the posterior parietal cortex (PPC) form the frontoparietal network, activated in humans during tasks that require attention. Subsequent studies in this thesis investigated the involvement of this network in 5C-CPT performance by using the immediate early gene c-Fos, a marker for neuronal activation. The number of c-Fos-positive neurones in PFC and PPC positively correlated with task engagement/vigilance (d prime). This finding further supports involvement of these regions in sustained attention, as well as the utility of the 5C-CPT as a highly translatable task. Electroencephalography in patients has shown that the attention-promoting dopamine re-uptake inhibitor methylphenidate (Ritalin), increases alpha oscillations in frontoparietal regions as well as increasing beta in frontal regions, which correlates with improved performance in attentive tasks. In the final study, local changes in low-frequency electrical oscillations of the PFC and PPC of the rat following an acute attention-promoting dose (1 mg/kg) of methylphenidate under urethane anaesthesia were analysed. Methylphenidate promoted alpha oscillations (8-12 Hz) in the PFC and high gamma oscillations (55-90 Hz) in the PPC and reduced delta (1-4 Hz), theta (4-8 Hz) and high gamma in the PFC. Alpha is linked to the suppression of irrelevant and selection of salient stimuli, which may be a mechanism by which methylphenidate promotes an attentive state. Clinical studies have positively correlated frontal theta to ADHD symptom severity and it is thought to be linked to underutilisation of attention. Therefore, reductions of theta in this experiment may also be associated with methylphenidate's ability to promote attention in the 5C-CPT. In conclusion, these studies support the use of a refined 5C-CPT as a translational task of relevance to conditions with inattention as a symptom, such as ADHD, schizophrenia and Alzheimer's disease. This thesis offers guidance for future work into how high and low attention in rodents interacts with pharmacological agents and the effects of encenicline show the potential of selective nicotinic alpha 7 agonists to improve attention. The presented work also shows that methylphenidate improves inattention and promotes alpha band oscillations in the PFC, which is a biomarker in need of further study. Additional research is needed to link these oscillations in anaesthetized animals to specific behaviours, but the work outlined here provides important progress towards understanding the interaction between inattention, pharmacology and the frontoparietal network.

Date of Award	31 Dec 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gigg (Supervisor), Wael El-Deredy (Supervisor), Joanna Neill (Supervisor) & Michael Harte (Supervisor)