Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress

Abstract

The pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT) are heterogeneous brainstem structures that contain cholinergic, glutamatergic, and GABAergic neurons. PPT/LDT neurons are suggested to modulate both cognitive and noncognitive functions, yet the extent to which acetylcholine (ACh) signaling from the PPT/LDT is necessary for normal behavior remains uncertain. We addressed this issue by using a mouse model in which PPT/LDT cholinergic signaling is highly decreased by selective deletion of the vesicular ACh transporter (VAChT) gene. This approach interferes exclusively with ACh signaling, leaving signaling by other neurotransmitters from PPT/LDT cholinergic neurons intact and sparing other cells. VAChT mutants were examined on different PPT/LDT‐associated cognitive domains. Interestingly, VAChT mutants showed no attentional deficits and only minor cognitive flexibility impairments while presenting large deficiencies in both spatial and cued Morris water maze (MWM) tasks. Conversely, working spatial memory determined with the Y‐maze and spatial memory measured with the Barnes maze were not affected, suggesting that deficits in MWM were unrelated to spatial memory abnormalities. Supporting this interpretation, VAChT mutants exhibited alterations in anxiety‐like behavior and increased corticosterone levels after exposure to the MWM, suggesting altered stress response. Thus, PPT/LDT VAChT‐mutant mice present little cognitive impairment per se, yet they exhibit increased susceptibility to stress, which may lead to performance deficits in more stressful conditions.—Janickova, H., Kljakic, O., Rosborough, K., Raulic, S., Matovic, S., Gros, R., Saksida, L. M., Bussey, T. J., Inoue, W., Prado, V. F., Prado, M. A. M. Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress. FASEB J. 33, 7018–7036 (2019). http://www.fasebj.org

Altered motor, anxiety-related and attentional task performance at baseline associate with multiple gene copies of the vesicular acetylcholine transporter and related protein overexpression in ChAT::Cre+ rats

“…Relatedly, previous studies showed that exposure to novel stimuli (i.e., novel environments) associates with cholinergic activation and increased ACh release (Thiel et al 1998; Giovannini et al 2001), while others showed that modulation of central cholinergic systems regulate emotional processes including anxiety and stress (Podhorna and Franklin 1999, 2000; Janickova et al 2019). However, the effects of ACh on anxiety-like behavior in rodents has proved complex, with increased ACh release that evoked both anxiolytic and anxiogenic reactions (File et al 1998, 2000), which may relate to brain region-specific configurations of ACh receptors (File et al 2000; Labarca et al 2001).…”

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity

“…Immunohistochemistry and immunofluorescence. Immunohistochemistry was performed as previously described 20 . In brief, the mice were anesthetized, the heart was perfused, and the brain was extracted and post-fixed overnight in 4% paraformaldehyde.…”

The role of acetylcholine in negative encoding bias: Too much of a good thing?

“…For instance, activating the mesopontine cholinergic inputs to dopamine neurons is sufficient to potentiate reactivity to stress (Fernandez et al, 2018). In addition, impairing the cholinergic output of the brainstem projections also increases susceptibility to stress and limits exploratory behavior, with limited cognitive effects (Janickova et al, 2019). The underlying mechanism for these cholinergic responses remains unclear and could involve improper habituation to environmental cues leading to anxiety‐like phenotype.…”