Trace Eyeblink Conditioning is Impaired in α7 but not in β2 Nicotinic Acetylcholine Receptor Knockout Mice

Abstract

Nicotinic acetylcholine receptors (nAChRs) are essentially involved in learning and memory. A neurobiologically and behaviorally well-characterized measure of learning and memory, eyeblink classical conditioning, is sensitive to disruptions in acetylcholine neurotransmission. The two most common forms of eyeblink classical conditioning – the delay and trace paradigms – differentially engage forebrain areas densely-populated with nAChRs. The present study used genetically modified mice to investigate the effects of selective nAChR subunit deletion on delay and trace eyeblink classical conditioning. α7 and β2 nAChR subunit knockout (KO) mice and their wild-type littermates were trained for 10 daily sessions in a 500-ms delay or 500-ms trace eyeblink conditioning task, matched for the interstimulus interval between conditioned stimulus and unconditioned stimulus onset. Impairments in conditioned responding were found in α7 KO mice trained in trace – but not delay – eyeblink conditioning. Relative to littermate controls, β2 KO mice were unimpaired in the trace task but displayed higher levels of conditioned responding in delay eyeblink conditioning. Elevated conditioned response levels in delay-conditioned β2 KOs corresponded to elevated levels of alpha responding in this group. These findings suggest that α7 nAChRs play a role in normal acquisition of 500 ms trace eyeblink classical conditioning in mice. The prominent distribution of α7 nAChRs in the hippocampus and other forebrain regions may account for these genotype-specific acquisition effects in this hippocampus-dependent trace paradigm.

High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept

“…Thus, in addition to protecting brain against secondary post-TBI injury, drugs that enhance α7 nAChR activation are expected to improve cognitive function and attention impairments in patients and animal models by increasing and partially restoring the endogenous cholinergic tone [6, 21, 29, 39]. In this regard, treatments with PNU are expected to benefit individuals with TBI and certain age-related cognitive deficits via multiple mechanisms and routes of action.…”

Effects of blockade of α4β2 and α7 nicotinic acetylcholine receptors on cue-induced reinstatement of nicotine-seeking behaviour in rats

“…The deletion of α 7 nAChRs was reported to impair responses in an appetitive learning task established by a natural reward, sucrose (Keller et al, 2005). A recent study showed that activation of α 7 nAChRs participated in trace eyeblink conditioning, a hippocampus-dependent conditioning process (Brown et al, 2010). …”

Cortical parvalbumin GABAergic deficits with α7 nicotinic acetylcholine receptor deletion: implications for schizophrenia

“…In humans reduced levels of α7 nAChR have been found in the prefrontal cortex and hippocampus of schizophrenia patients in postmortem studies (Freedman et al, 1995; Leonard et al, 1996; Freedman et al, 1997; Freedman et al, 2000; Freedman and Leonard, 2001; Freedman and Goldowitz, 2010; Ross et al, 2010). In animals loss of the α7 nAChR causes analogous abnormalities including impaired attention, working-memory and learning (Fernandes et al, 2006; Young et al, 2007; Levin et al, 2009; Brown et al, 2010; Young et al, 2011; Hellier et al, 2012). These findings suggest crucial roles of α7 nAChR in cortical circuit function and dysfunction.…”