Some rats [sign-trackers (STs)] are especially prone to attribute incentive salience to reward cues, relative to others [goal-trackers (GTs)]. Thus, reward cues are more likely to promote maladaptive reward-seeking behavior in STs than GTs. Here, we asked whether STs and GTs differ on another trait that can contribute to poor restraint over behavior evoked by reward cues. We report that, relative to GTs, STs have poor control over attentional performance, due in part to insufficient cholinergic stimulation of cortical circuitry. We found that, relative to GTs, STs showed poor performance on a sustained attention task (SAT). Furthermore, their performance fluctuated rapidly between periods of good to near-chance performance. This finding was reproduced using a separate cohort of rats. As demonstrated earlier, performance on the SAT was associated with increases in extracellular levels of cortical acetylcholine (ACh); however, SAT performance-associated increases in ACh levels were significantly attenuated in STs relative to GTs. Consistent with the view that the modulatory effects of ACh involve stimulation of α4β2* nicotinic ACh receptors (nAChRs), systemic administration of the partial nAChR agonist ABT-089 improved SAT performance in STs and abolished the difference between SAT-associated ACh levels in STs and GTs. Neither the nonselective nAChR agonist nicotine nor the psychostimulant amphetamine improved SAT performance. These findings suggest that individuals who have a propensity to attribute high-incentive salience to reward cues also exhibit relatively poor attentional control. A combination of these traits may render individuals especially vulnerable to disorders, such as obesity and addiction.

The cognitive control of attention involves maintaining task rules in working memory (or "online"), monitoring reward and error rates, filtering distractors, and suppressing prepotent, and competitive responses. Weak attentional control increases distractibility and causes attentional lapses, impulsivity, and attentional fatigue. Levels of tonic cholinergic activity (changes over tens of seconds or minutes) modulate cortical circuitry as a function of the demands on cognitive control. Increased cholinergic modulation enhances the representation of cues, by augmenting cue-evoked activity in thalamic glutamatergic afferents, thereby increasing the rate of detection. Such cholinergic modulation is mediated primarily via α4β2* nicotinic acetylcholine receptors. Animal experiments and clinical trials in adult patients with ADHD indicate that attentional symptoms and disorders may benefit from drugs that stimulate this receptor. Tonic cholinergic modulation of cue-evoked glutamatergic transients in prefrontal regions is an essential component of the brain's executive circuitry. This circuitry model guides the development of treatments of deficits in attentional control.

Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test. Importantly, long-term BDNF delivery did not alter normal behaviors such as general activity or sleep/wake patterns. Detailed immunohistochemical analyses revealed that the neurological benefits of BDNF were associated with several anatomical changes, including reduction in degenerating cells and normalization of hippocampal volume, neuronal counts (including parvalbumin-positive interneurons), and neurogenesis. In conclusion, the present data suggest that BDNF, when continuously released in the epileptic hippocampus, reduces the frequency of generalized seizures, improves cognitive performance, and reverts many histological alterations associated with chronic epilepsy. Thus, ECB device-mediated long-term supplementation of BDNF in the epileptic tissue may represent a valid therapeutic strategy against epilepsy and some of its co-morbidities.