Executive and social behaviors under nicotinic receptor regulation

Abstract

Nicotine enhances several cognitive and psychomotor behaviors, and nicotinic antagonists cause impairments in tasks requiring cognitive effort. To explore the contribution of nicotinic receptors to complex cognitive functions, we developed an automated method to investigate sequential locomotor behavior in the mouse and an analysis of social behavior. We show that, in the beta2-/- mutant, the high-order spatiotemporal organization of locomotor behavior, together with conflict resolution and social interaction, is selectively dissociated from low-level, more automatic motor behaviors. Such deficits in executive functions resemble the rigid and asocial behavior found in some psychopathological disorders such as autism and attention deficit hyperactivity disorder.

Fig. 1.

Spatial learning measured in a modified cross maze in which a place strategy was reinforced. (a) The location of the food reward (goal) was constant, and the position of the animal to reach the goal (west or east) was variable. (b) After completion of learning, a test phase evaluated whether mice used intramaze and/or extramaze cues to reach the goal. (c) β2^-/- mice reached the goal more quickly than WT for days 1–4 [group effect: F(1,14) = 14.9 and P = 0.0017; interaction group × session effect: F(6,84) = 4.76 and P = 0.0003; post hoc analyses (t test, df = 14): day 1 (t = 3.8 and P = 0.018), day 2 (t = 4.21 and P = 0.009), and day 3 (t = 2.46 and P = 0.028)] but showed no significant difference for subsequent days including the test phase (all P values > 0.06).

Fig. 2.

Exploratory behavior in a circular open field. (a) Balance between navigatory (Left) and exploratory (Right) behaviors is statistically different between WT and KO mice [t = 2.63 and 3.78, df = 38; P = 0.012 and 0.0005, respectively]. (b Left) Density of trajectories in the arena for WT (Upper) and β2^-/- (Lower) mice. (Right) The density of segments of slow trajectories shows accumulation in the center for WT (Upper) but not β2^-/- (Lower) mice. (c) Significant difference for entropy of conditional probability transition from the BF state between WT and KO (t test, df = 18, t = 4.05, and P = 0.0008). (d) Modification of entropy from BF indicated that β2^-/- mice favor transition from BF to AF instead of BS (indicated by dashed line). This explained the reduction of density of slow trajectories in the center of the arena observed in β2^-/- mice.

Fig. 3.

Exploration of two different objects in the open field. Objects remained at the same place for sessions 1–3, and their places were exchanged for the test. (a Upper) The duration of exploration of the objects' areas was not different for WT and KO animals for sessions 1 and 2 and test but differed for session 3 {repeated measures of variance for the four sessions revealed a significant group effect [F(1,10) = 6.28 and P = 0.03) and a significant session effect [F(3,30) = 3.77 and P = 0.02]}. Post hoc analyses demonstrated that the two groups differed only for session 3, i.e., before spatial change (t = 3.6, df = 10, and P = 0.005; all other P values > 0.13). (a Lower) A similar result was obtained with entropy {repeated measures of variance for the four sessions revealed a significant group effect [F(1,10) = 7.09 and P = 0.024] and a marginally significant session effect [F(3,30) = 2.8 and P = 0.057]}. Post hoc analyses demonstrated that the two groups differed only for session 3, i.e., before the spatial change (t = 3.53, df = 10, and P = 0.0054; all other P values > 0.08). WT mice exhibited habituation, which is absent in β2^-/- mice. (b) Illustration of trajectories at slow speed at the center of the open field (red points) for WT (Upper) and KO (Lower) mice for session 3.

Fig. 4.

Mice were subjected to conflict-resolution situations. (a) During spatial learning, objects were inserted in the maze (see Methods for details). The two groups differed significantly during learning {group effect: F(1,12) = 13.92 and P = 0.003; session effect: [F(10,120) = 9.1 and P < 0.0001]; and interaction group × session: [F(10,120) = 2.83 and P = 0.0034]}. The post hoc Student's t test indicated that the two groups were different for the first session (t = 3.0, df = 12, and P = 0.01) and the two first sessions with objects (t = 2.57 and 3.1, df = 12, and P = 0.024 and 0.0097, respectively) but not for the subsequent sessions with the same-sized or smaller object. The time to reach the goal was different for the two groups when a bigger object was inserted within the maze (t = 2.54, df = 12, and P = 0.026) or for a challenge (Fig. 1b)(t = 2.25, df = 12, and P = 0.029). (b) Sequences of social interactions between a test resident mouse and a social intruder. The number of behavioral sequences differed significantly between KO and WT mice for the first and fourth types of sequence (t =,df = 18, and P = 0.046 and 0.0009, respectively).