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. Because stimulation of NMDA receptors in the shell of the nucleus accumbens 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 intracortical infusions of the cholinotoxin 192 IgG-saporin, attenuated the beneficial effects of NMDA on dSAT performance. 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.

Figure 1.

Distractor-induced impairment in attentional performance and prefrontal ACh release in the presence and absence of a distractor. a, The SAT consists of randomly ordered signal (light signals 500, 50, or 25 ms long) and nonsignal events, spaced by 9 ± 3 s. Two seconds after an event, levers are made available and animals need to respond within 4 s. Following a lever press or after 4 s, levers are withdrawn. b, Hits and correct rejections, but not misses and false alarms, are rewarded (note that arrows indicating the four response types in a are color-coded and match arrows in b). Sessions lasted 40 min and were blocked post hoc into five 8 min blocks of trials (t1–t5). c, For dSAT testing, the distractor (chamber lights flashing on and off at 0.5 Hz) occurred during blocks 2 and 3 in experiments involving monitoring ACh release using microdialysis, and blocks 3 and 4 following intracranial infusions, conducted over the first 2 min of block 2. The vertical red and black bars illustrate a random sequence of signal and nonsignal trials (signal duration indicated by the length of the red bars). Intracranial infusions into the shell or core of the NAc were conducted remotely to limit interfering with the animals' performance. Therefore, undisturbed block 1 performance data were obtained from all animals before infusions into the NAc core or shell and before the presentation of the distractor during dSAT performance. d, In the absence of a distractor (SAT; n = 6), performance varied with signal duration and remained stable over the five task blocks (t1–t5). e, Presentation of the distractor during task blocks 2 and 3 transiently impaired performance. The distractor-induced impairment in performance (dSAT; n = 9) was due to decreases in both the relative number of hits (f) and correct rejections (g). Errors of omission remained low and were not significantly affected by the distractor (Results). During the postdistractor blocks, animals' performance recovered. h, SAT performance evoked a steep initial increase in ACh release in the medial PFC. Release levels remained stable throughout the remainder of the performance session. Presentation of the distractor further increased ACh release [b1–b3 depict baseline collections before task onset, t1–t5 depict the five task blocks, and at1–at4 indicate data from four collections following completion of the task (8 min/collection)]. i, The severity of the distractor-induced impairment of performance was significantly correlated with distractor-induced increases in cholinergic activity. The abscissa of this graph depicts the differences between t1 and t2/t3 dSAT scores, with larger numbers indicating more severe impairments. Thus, higher increases in ACh release were correlated with less severe distractor effects on performance. *p < 0.05; LSD.

Figure 2.

Reconstruction of the infusion sites in the shell (top) and core (bottom) of the NAc and estimation of the infusion spread based on infusions of Fluoro-Gold (see Materials and Methods for details). Similar to our earlier studies that involved infusion of compounds into the shell of the NAc (Himmelheber et al., 2000), the fluorophore occupied an asymmetrical space, likely confined in part by structural boundaries (see also Allen et al., 2008). Infusions into the shell were intended to occupy the more rostral half of this subregion (see Materials and Methods; Faure et al., 2010).

Figure 3.

Effects of infusions of NMDA into the NAc shell (n = 28) on attentional performance in the absence (SAT; b, e, h, k) or presence (dSAT; c, f, i, l) of a distractor (task blocks 3 and 4). The graphs in the left column (a, d, g, j) depict the animals' performance during the first block of trials, before infusions into the NAc shell of performing animals and for both task conditions. In SAT performing animals (middle column), NAc infusions did not affect performance except for an increase in omissions caused by the highest dose of NMDA (k). In contrast, in dSAT performing animals, infusions of NMDA restored the animals' performance (dSAT score) to a level statistically similar to the performance of vehicle-treated animals in the absence of a distractor. This effect was due to the combined effects on hits (f) and correct rejections (i), although neither individual measure was solely responsible for the overall effect of NMDA. k, l, In SAT and dSAT performing animals, the highest dose of NMDA increased omissions (*p < 0.05; **p < 0.01; LSD).

Figure 4.

Removal of cholinergic input to the mPFC or PPC by infusions of the immunotoxin 192 IgG-saporin into these cortical regions. The schematic coronal sections on the left indicate the areas in which ChAT-positive fibers were counted (see black squares representing the location of the 200 × 200 μm counting areas; not drawn to scale; anterior–posterior levels based on bregma). The microphotographs exemplify ChAT-positive fibers and cells in the counting regions for sham-operated, PFC-deafferented, and PPC-deafferented animals (scale for all photomicrographs is indicated in the lower right microphotograph). The microphotographs showing deafferented mPFC or PPC indicate the presence of residual ChAT-positive, large bipolar cortical interneurons. These neurons do not express p75 receptors and thus are not lesioned by the immunotoxin (Heckers et al., 1994). The function of these neurons is poorly understood (von Engelhardt et al., 2007). The bar graphs on the right indicate ChAT-positive fiber counts and the result of multiple comparisons (LSD) based on significant effects of group and interactions between group and region as indicated by ANOVA (F values > 3.16, p < 0.001). Collectively, these analyses confirmed the efficacy and regional selectivity (mPFC vs PPC) of the removal of cholinergic input. IL, Infralimbic cortex; LPtA, lateral parietal association cortex; M1, primary motor cortex; PrL, prelimbic cortex; RS, retrosplenial (agranular) cortex; VI1/2, primary/secondary visual cortex.

Figure 5.

Infusions of NMDA into the shell of the NAc restored the performance during the distractor blocks (t3, t4) in animals that received sham surgeries for cholinergic deafferentation of the prefrontal and posterior parietal cortex (a, b), but not following removal of prefrontal (c) or posterior parietal (d) cholinergic inputs (n = 19). a, Infusions of NMDA (0.33 nmol/hemisphere) restored the animals' dSAT performance (t3, t4), reproducing the effect observed in nonoperated animals. However, in this case, the effects on hits (b), but not correct rejections (data not shown), also reached significance. The inset in b illustrates the intact cortical cholinergic input system arising from the basal forebrain (BF), BF afferent systems originating from PFC, NAc, and ventral tegmentum (VTA), as well as the projections of the VTA to PFC and NAc, color coded to reflect type of projection: blue, glutamate (GLU); green, GABA; red, acetyleholine (ACh); yellow, dopamine (DA). The corresponding insets in c and d illustrate the removal of PFC and PPC cholinergic projections, respectively. In deafferented animals, NMDA infusions failed to benefit dSAT performance (*p < 0.05; LSD).