Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors

Abstract

Acetylcholine (ACh) signaling underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. Alterations in ACh signaling are involved in the pathophysiology of multiple neuropsychiatric disorders. In the central nervous system, ACh transmission is mainly guaranteed by dense innervation of select cortical and subcortical regions from disperse groups of cholinergic neurons within the basal forebrain (BF; e.g., diagonal band, medial septal, nucleus basalis) and the pontine-mesencephalic nuclei, respectively. Despite the fundamental role of cholinergic signaling in the CNS and the long standing knowledge of the organization of cholinergic circuitry, remarkably little is known about precisely how ACh release modulates cortical and subcortical neural activity and the behaviors these circuits subserve. Growing interest in cholinergic signaling in the CNS focuses on the mechanism(s) of action by which endogenously released ACh regulates cognitive functions, acting as a neuromodulator and/or as a direct transmitter via nicotinic and muscarinic receptors. The development of optogenetic techniques has provided a valuable toolbox with which we can address these questions, as it allows the selective manipulation of the excitability of cholinergic inputs to the diverse array of cholinergic target fields within cortical and subcortical domains. Here, we review recent papers that use the light-sensitive opsins in the cholinergic system to elucidate the role of ACh in circuits related to attention and emotionally salient behaviors. In particular, we highlight recent optogenetic studies which have tried to disentangle the precise role of ACh in the modulation of cortical-, hippocampal- and striatal-dependent functions.

Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits

“…The current in vivo electrophysiological studies also provide support to the notion that ACh can act rapidly and exert prolonged changes in network excitability (Chen et al 2015, Eggermann et al 2014, Luchicchi et al 2014, Sarter et al 2014). In the BLA brief photo-activation of cholinergic terminal fields elicited rapid changes in action potential firing (τ delay = 62 msec; Fig 3D) or in membrane potential (τ delay =10–100 msec) and slower but prolonged increases in firing rates of putative principal neurons (Fig 3, 4).…”

“…Recall of either highly aversive or appetitive events engages distributed brain networks whose activity is tuned by various neuromodulators, including acetylcholine (ACh; (Hasselmo and Sarter 2011, Hermans et al 2014, LeDoux 2012, Luchicchi et al 2014, Picciotto et al 2012). Cholinergic signaling has long been implicated in attending to and remembering emotionally potent experiences, but the precise role of ACh signaling in mnemonic processing of highly salient events has remained elusive (Dani and Bertrand 2007, Hasselmo and Sarter 2011, Luchicchi et al 2014, Sarter et al 2014). The major challenge to dissecting the role of endogenous ACh in the formation and retention of potent memories has been the inability to selectively and reversibly manipulate the activity of cholinergic inputs, which tend to be sparsely distributed, extensively arborized and intermingled with projections of other transmitter phenotypes (Wu et al 2014).…”

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…Many of the recent studies that have demonstrated a central role of cholinergic signaling in both attentional and memory related circuits and behaviors have been made possible by the advent of optogenetics for the selective stimulation of BF cholinergic neurons and their terminal fields (Jiang et al, 2014; Luchicchi et al, 2014). An additional benefit of the technology is its illumination (pun intended) of the extent to which many transmitters – including ACh - are co-stored and, under some stimulation conditions, may be co-released with other transmitters (e.g.…”

Cholinergic excitation complements glutamate in coding visual information in retinal ganglion cells

“…; Luchicchi et al . ). However, recent evidence suggests that ACh can be a primary driver of activity, complementing glutamate (Beierlein, ; Sarter et al .…”