Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

Abstract

Recent work continues to place cholinergic circuits at center stage for normal executive and mnemonic functioning and provides compelling evidence that the loss of cholinergic signaling and cognitive decline are inextricably linked. This Review focuses on the last few years of studies on the mechanisms by which cholinergic signaling contributes to circuit activity related to cognition. We attempt to identify areas of controversy, as well as consensus, on what is and is not yet known about how cholinergic signaling in the CNS contributes to normal cognitive processes. In addition, we delineate the findings from recent work on the extent to which dysfunction of cholinergic circuits contributes to cognitive decline associated with neurodegenerative disorders.

Figure 1. Functionally modular projection patterns, exotic axonal morphologies and diverse ACh release-receptor interactions contribute to complex spatio-temporal dynamics of ACh signaling by basal forebrain cholinergic neurons

(see text and Reviews by Munoz & Rudy, 2014; Picciotto et al., 2012; Sarter, 2016; Zaborzsky et al., 2015). A. Schematic of projection patterns of basal forebrain cholinergic neurons. Left hand side: schematic of coronal sections indicating the approximate anterior to posterior and medial to lateral distribution of the HDB (horizontal limb of the diagonal band) and NB/SI (Nucleus Basalis/Substantia innominata). Anterior medial BFCNs within these nuclear groups project to medial frontal cortical targets whereas posterior located cholinergic neurons project to more posterior targets such as the BLA and perirhinal cortex. Right hand side: Medial septal (MS) and vertical limb of the diagonal band (VDB) neurons provide cholinergic input to the hippocampus and entorhinal cortex. B. and C. Axonal morphology of fully reconstructed basal forebrain cholinergic neurons and the extensive terminal arborization formed in cortex. Adapted with permission from Wu et al., 2014 https://creativecommons.org/licenses/by/3.0/. D. Schematic representation of both point-to-point (focused, triangular) and en passant (broad circular) mechanisms by which ACh is released in the CNS, thereby effecting both glutamatergic (green) and GABAergic (blue) neuronal excitability. Such release profiles may correspond to the more rapid and transient responses and the slower, longer lasting modulatory effects of ACh, respectively (see text for discussion). Also shown are representative distributions of both muscarinic (depicted as 7 TM squiggles) and nicotinic (represented as single tubes) AChRs at pre, post and peri synaptic sites. Both mAChR and nAChR subtypes at each of these locations contribute to the direct and indirect mechanisms by which ACh can alter synaptic excitability (see text for discussion).

Figure 2. Schematic Representation of Cholinergic Inputs and Signaling in Cortical, Hippocampal and Amygdala circuits

(see text) from Bloem et al., 2014.; Kim et al., 2016; Nelson & Mooney, 2016; Jiang et al., 2016; Munoz & Rudy, 2014; Gu & Yakel, 2011; Cheng & Yakel, 2016. Numerous studies now converge on specific mechanisms of ACh release and profiles of AChR activation in different brain areas. Each schematic represents a summary of recent studies of the cholinergic projection neurons (below) and consequent signaling effects of ACh in local circuit activity in (above; left to right) the Prefrontal Cortex (PFC), Auditory cortex (Au Ctx), hippocampus and (basal) amygdala.

Figure 3. Schematic of BFCN interaction with attention related circuitry

Task oriented information from the PFC is transmitted to the basal forebrain, which signals to sensory cortex where cholinergic signaling causes decorrelation (Chen et al., 2015; Goard & Dan, 2009; Kalmbach et al., 2012; Kalmbach & Waters, 2014; Pinto et al., 2013; Runfeldt et al., 2014; Thiele et al., 2012; Kim et al., 2016) and enhances response reliability (Cohen & Maunsell, 2009; Mitchell et al. 2009). Once a task relevant stimulus is detected in the sensory cortex, cholinergic signaling from the basal forebrain to the PFC is stimulated and transient ACh release within the PFC signals cue detection (Sarter et al., 2016a; Parikh et al., 2007; Howe et al., 2013).

Figure 4. Alterations to Cholinergic Projections and Circuits in Dementia

A. Trajectory of Alzheimer’s Disease Dementia from early to late stage (see text). Schematic representation of current concepts of cholinergic axonal retrograde death, superimposed on schematic that indicates the increasing extent of affected brain areas in blue. B. Cellular mechanisms of cholinergic neuronal loss and subsequent disruption of target hippocampal & cortical domains. Possible mechanisms thought to underlie early loss of cholinergic projections in an animal model of AD-like dementia: Aβ induced excitotoxicity mediated by interaction with α7* nAChRs (Hascup & Hascup, 2016; Liu et al., 2016; Wu et al., 2016), and impaired neurotrophin–induced retrograde transport via Rab5 endosome enlargement (Xu et al., 2015). Images for A adapted from human brain atlas (Hawrylycz et al., 2012)