Delayed procedural learning in α7-nicotinic acetylcholine receptor knockout mice

Abstract

The α7-nicotinic acetylcholine receptor (nAChR) has long been a procognitive therapeutic target to treat schizophrenia. Evidence on the role of this receptor in cognition has been lacking, however, in part due to the limited availability of suitable ligands. The behavior of α7-nAChR knockout (KO) mice has been examined previously, but cognitive assessments using tests with cross-species translatability have been limited to date. Here, we assessed the cognitive performance of α7-nAChR KO and wild-type (WT) littermate mice in the attentional set-shifting task of executive functioning, the radial arm maze test of spatial working memory span capacity and the novel object recognition test of short-term memory. The reward motivation of these mutants was assessed using the progressive ratio breakpoint test. In addition, we assessed the exploratory behavior and sensorimotor gating using the behavioral pattern monitor and prepulse inhibition, respectively. α7-nAChR KO mice exhibited normal set-shifting, but impaired procedural learning (rule acquisition) in multiple paradigms. Spatial span capacity, short-term memory, motivation for food, exploration and sensorimotor gating were all comparable to WT littermates. The data presented here support the notion that this receptor is important for such procedural learning, when patterns in the environment become clear and a rule is learned. In combination with the impaired attention observed previously in these mice, this finding suggests that agonist treatments should be examined in clinical studies of attention and procedural learning, perhaps in combination with cognitive behavioral therapy.

Dissociable Deficits of Executive Function Caused by Gestational Adversity are Linked to Specific Transcriptional Changes in the Prefrontal Cortex

“…A baseline sex difference was observed with females showing an overall lower level of performance (fewer overall responses), which also resulted in an increased number of FR1 training sessions in females. The PR schedule was as previously described (Young et al, 2011) and was administered after all animals acquired FR1, and analyzed with ANOVA. Following PR, animals were transitioned to an FR1 where a response at any hole was rewarded in preparation for 5-choice testing.…”

“…Both male and female HF offspring responded at lower levels and were delayed at meeting criterion (Figure 1c), whereas LP offspring were not significantly different than controls. Once the nose-poke response was learned, PR performance was used to assess motivation to work for reward by increasing the number of responses needed to elicit a reinforcer (Young et al, 2011). Both male and female HF offspring were less motivated, seen as reduced breakpoints (Figure 1d).…”

Translational Rodent Paradigms to Investigate Neuromechanisms Underlying Behaviors Relevant to Amotivation and Altered Reward Processing in Schizophrenia

“…45 The dopaminergic system may be less important for cognitive than physical effort given that dopamine receptor antagonists reduced effort in the latter 46,86 but not the former. 46 Additionally, mice without alpha7 nAChRs exhibited normal physical effort motivation but impaired reward-associative learning, 87 despite such mice exhibiting normal learning in aversively motivated environments. 88 Other differences include the need of the dorsal striatum in rats performing an effort-based decision-making task 89,90 but not in the PRBP.…”

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…All test mice were the F1 generation mice with the same genetic background (Ji et al, 2013;Zhou et al, 2010), were 3 months old at the time of testing, and weighed between 21 and 28 g. All animals were group housed (maximum four/cage) and maintained in a temperature-controlled vivarium (21 ± 1°C) with a reversed 12 h day/night cycle (lights off at 0700 h and on at 1900 h). During training, mice were food restricted to maintain weight at 85% of their free-feeding weight, as is commonly used during reward-learning training (Young et al, 2011). For quantification of GlyT-1 levels, 8 WT and 7 Hyp mice at 5 months were used (see Supplementary Methods).…”