Conditioned and Unconditioned Stimuli Increase Frontal Cortical and Hippocampal Acetylcholine Release: Effects of Novelty, Habituation, and Fear

Abstract

Recent evidence showing that basal forebrain cholinergic neurons with projections to the frontal cortex and hippocampus are activated by behaviorally salient stimuli suggests that these neurons are involved in arousal and/or attentional processes. We sought in the present experiments to test this hypothesis by examining whether unconditioned stimuli (a tone and flashing light) that normally increase cortical nad hippocampal acetylcholine (ACh) release would fail to do so after habituation (i.e., repeated presentation with no programmed consequences). In addition, the extent to which presentation of these stimuli would continue to increase ACh release when they had previously been paired with an aversive stimulus was investigated. Three experimental groups were used: habituation, novel stimuli, and conditioned fear. Subjects in each of these groups were placed in a training apparatus for twelve 200 min sessions. While the habituation group received extensive exposure to the tone and light during the training sessions, subjects in the novel stimuli group were placed in the apparatus but were never exposed to the tone or light during these sessions. The conditioned fear group was treated identically to the habituation group, with the addition that the tone and light were paired with footshock. On completion of these training schedules, all animals were implanted with microdialysis probes in the frontal cortex and hippocampus. Two days later, they were placed in the apparatus and the tone and light were presented to all subjects during microdialysis. In the novel stimuli group, the tone and light (unconditioned stimuli) produced significant increases in frontal cortical and hippocampal ACh release. Similarly, in the conditioned fear group, presentation of the tone and light (conditioned stimuli) also significantly increased ACh release in frontal cortex and hippocampus. In contrast, in the habituation group the tone and light failed to significantly enhance ACh release in either structure. During the test session, the tone and light elicited a variety of arousal- and fear-related behaviors in the novel stimuli and conditioned fear groups. In contrast, subjects in the habituation group generally failed to respond to these stimuli. These data indicate that cortically and hippocampally projecting basal forebrain cholinergic neurons are activated by conditioned and unconditioned stimuli that produce arousal in rats (novelty or conditioned fear). In contrast, presentation of these stimuli to habituated animals fails to enhance ACh release. These findings are consistent with a growing body of information indicating that ACh release in the cortex and hippocampus is reliably activated by behaviorally relevant stimuli. They also provide strong support for the hypothesis that cholinergic neurons in the basal forebrain are involved in arousal and/or attentional processes.

Hippocampal networks habituate as novelty accumulates

“…However, if individuals are exposed to novelty in the absence of behaviorally relevant outcomes, as they were in our current study, the salience of novelty and the associated neurophysiological response should habituate (Sokolov 1963). As noted above, previous studies have demonstrated habituation of the HPC in prolonged exposure to a single novel environment (Wilson and Rolls 1990a,b;Acquas et al 1996;Giovannini et al 2001) or repeated exposures to the same stimuli (Henson et al 2003), as well as fear-predicting and fear-evoking stimuli (Buchel et al 1999;Fischer et al 2003). Previous research has also demonstrated that HPC responses are sensitive to experimentally instructed expectations about the value of information (Adcock et al 2006;Murty et al 2012) that should affect the salience of novelty (Wittmann et al 2007;Bunzeck et al 2010).…”

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

“…Exposure to a novel environment has been shown to transiently increase cholinergic neurotransmission in the hippocampus. [35][36][37][38][39] In M2-KOs and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration as compared to WT mice. This enhancement in the acetylcholine response in the KO mice could be a consequence of a number of distinct phenomena, including an increase in acetylcholine synthesis or a reduction in catabolism.…”

“…Increases in cholinergic activity in the forebrain upon exposure to novelty (novel environment or other unconditioned stimulus such as light or tone) are believed to reflect primarily arousal by and/ or attention to behaviorally salient stimuli [37][38] and to a lesser extent exploratory activity or fear. 36,38 Increases in hippocampal acetylcholine release produced by unconditioned stimuli are significantly reduced by between-and within-session habituation. 38 Novelty-induced increases in acetylcholine release are transient, peaking at the first 10-15 min after presentation of the stimulus and steadily decreasing afterwards.…”

Neural responses to salient visual stimuli

“…This type of conditioning has been demonstrated across the phylogenetic scale from gastropod molluscs (Hawkins et al 1983) to humans (Hodes et al 1985), and the synaptic changes involved (Kandel & Schwartz 1982) represent one of the simplest forms of value-dependent neural plasticity (Friston et al 1994). In mammals, this plasticity of neural response appears to involve neuromodulatory cholinergic projections, predominantly from the nucleus basalis of Meynert in the basal forebrain (Pirch et al 1992 ;Hars et al 1993 ;Acquas et al 1996).…”