Cholinergic modulation of cognitive process: behavioural, molecular and cellular approach studying the sustained attention performance on rats

Cholinergic projections from the nucleus basalis of Meynert (medial wall of globus pallidus), substantia innominata (ventral to the globus pallidus) and the horizontal limb of the diagonal band (collectively termed basal forebrain, BF) innervate the entire cortical mantel. These inputs are critically involved in the mediation of attentional functions such as the detection, selection and processing of stimuli. However, the exact mechanisms through which telencephalic cholinergic systems mediate attention remain poorly understood. The scope of this thesis was to better understand the cholinergic mechanisms underlying the attentional processes. More specifically, the role of the ascending neuronal projection system, particularly the cholinergic projections arising from the basal forebrain (BF) to the medial prefrontal cortex (mPFC) has been investigated. Different approaches has been utilized: (1) behavioural, testing the effect of acute and sub chronic nicotine on the sustained attention task on rats; (2) cellular, combining attentional measures obtained by behavioural sustained attention task performance with surgical manipulations on rats. 192 IgG-saporin or Ibotenic Acid or vehicle were intracranial infused into the rats’ mPFC. (3) molecular, detecting and quantifying the potassium- and nicotine- evoked cholinergic activity in vivo in terms of extracellular levels of choline and acetylcholine with sub- second temporal resolution using enzyme-selective microelectrodes coated with acetylcholinesterase + choline oxidase (AChE+ChOx) versus choline oxidase alone (ChOx-only). Summarising, from these studies it emerged that nicotine treatment at the dose 0.32 mg/kg/ml robustly enhanced the attentional performance during the post-distractor period on the sustained attention task. Sub- chronic nicotine treatment at the dose 0.35 mg/kg/ml for 15 consecutive days decreased transiently the attentional performance (on day 1 and day 2) on the sustained attention task. During the withdrawal period (where all the animals received saline for three consecutive days) and during challenge- sessions with either saline or nicotine 0.35 mg/kg/ml treatment in presence or absence of distractor during the second and third blocks of the session, the animals did not change the attentional performance on sustained attention task. Ibotenic Acid lesioned- animals showed decreased attentional performance on sustained attention task compared to IgG-saporin- and sham- lesioned animals. During distractor sessions, Ibotenic Acid lesioned- animals were not able to recover the attentional impairment at the post- distractor period, whereas 192 IgG- saporin- lesioned animals did not show any apparent difference in terms of performance, in spite of significant cholinergic fibres destruction. Potassium- and nicotine- evoked cholinergic signals recorded throughout the entire dorsal- ventral extent of the mPFC using enzyme- selective ceramic- based microelectrodes did not differ between AChE+ChOx and ChOx-only coated recording sites. Taken together, these data showed that the combination between behavioural, cellular and molecular aspects of the attentional process can be a valid tool to model the complexities of cognitive processes and to potentially better understand the underlying mechanisms.