Enhanced Control of Attention by Stimulating Mesolimbic-Corticopetal Cholinergic Circuitry

Abstract

Sustaining and recovering attentional performance requires interactions between the brain’s motivation and attention systems. The first experiment demonstrated that in rats performing a sustained attention task (SAT), presentation of a distractor (dSAT) augmented performance-associated increases in cholinergic neurotransmission in prefrontal cortex (PFC). Because stimulation of NMDA receptors in the shell of the nucleus accumbens (NAC) activates PFC cholinergic neurotransmission, a second experiment demonstrated that bilateral infusions of NMDA into the NAC shell, but not core, improved dSAT-performance to levels observed in the absence of a distractor. A third experiment demonstrated that removal of prefrontal or posterior parietal cholinergic inputs, by intra-cortical infusions of the cholinotoxin 192 IgG saporin, attenuated the beneficial effects of NMDA on dSAT perfomance. Mesolimbic activation of cholinergic projections to the cortex benefits the cognitive control of attentional performance by enhancing the detection of cues and the filtering of distractors.

Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia

“…Intra-NAC NMDA administration facilitates attentional performance under conditions of enhanced demands on performance, suggesting that NAC-cholinergic interactions mediate the motivated recruitment of attention systems (St Peters et al, 2011). This evidence is consistent with the hypothesis that stimulation of NAC NMDA receptors mimics the top-down PFC-NAC activation of the BFCS, an activation that is critical for the recruitment of motivation to stay on task when faced with enhanced cognitive load.…”

“…In intact animals, perfusion of NMDA into the NAC shell markedly stimulates basal ACh levels in PFC (Zmarowski et al, 2005), and this NMDA modulation is facilitated by concurrent activation of D1 receptors in NAC (Zmarowski et al, 2005) and inhibited by stimulation of D2 receptors (Brooks et al, 2007). Recently, we demonstrated that infusions of NMDA into NAC shell rescued the falling performance of rats performing in a sustained attention task when faced with distractors that otherwise severely impair attentional processing (St Peters et al, 2011). Thus, NMDA-mediated elevation of prefrontal ACh levels serves as a bioassay for testing the integrity and efficacy of topdown control mechanisms that are essential for maintaining goal-directed behavior.…”

Cortical cholinergic signaling controls the detection of cues

“…Our current circuitry model suggests that separate cholinergic neuromodulatory activity, acting on a scale of minutes, can influence the generation of transients via stimulation of nicotinic ACh receptors expressed by thalamic glutamatergic terminals (37,38). Cholinergic neuromodulation varies as a function of levels of top-down attentional control and is driven in part by mesolimbic activity (39). This hypothesis predicts that the loss of reward caused by distractors and associated error rates alters the likelihood for, and perhaps also the dynamics of, cholinergic transients.…”

Transient Inactivation of the Neonatal Ventral Hippocampus Impairs Attentional Set-Shifting Behavior: Reversal with an α7 Nicotinic Agonist

“…This dysregulation may contribute to the performance deficits in the task given the significant role that cortical cholinergic transmission has in attentional processing (Hasselmo and Sarter, 2011;Sarter et al, 2005) and, more specifically, the importance of the mesolimbic recruitment of prefrontal ACh release to maintain performance as the conditions of the task become more challenging (St Peters et al, 2011). Finally, in a series of studies using infusions of TTX into VH at PD7, Louilot and colleagues have reported abnormalities in accumbens dopaminergic transmission related to deficits in performance in a latent inhibition task (Meyer et al, 2009;Peterschmitt et al, 2008).…”

“…Through integration of these inputs, the NAC influences PFC activation by various pathways, including direct modulation from the basal forebrain cortical cholinergic system (BFCS; Zaborszky and Cullinan, 1992). We previously demonstrated that glutamatergic excitation of the NAC can evoke acetylcholine (ACh) release in the PFC (Zmarowski et al, 2005;Brooks et al, 2007), thereby recruiting interactions between motivational and attentional mechanisms necessary to ensure stable attentional performance when demands on cognitive control are high (St Peters et al, 2011).…”