Cholinergic Modulation of Cortical Microcircuits Is Layer-Specific: Evidence from Rodent, Monkey and Human Brain

Abstract

Acetylcholine (ACh) signaling shapes neuronal circuit development and underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. During behavior, activation of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) by ACh alters the activation state of neurons, and neuronal circuits most likely process information differently with elevated levels of ACh. In several brain regions, ACh has been shown to alter synaptic strength as well. By changing the rules for synaptic plasticity, ACh can have prolonged effects on and rearrange connectivity between neurons that outlasts its presence. From recent discoveries in the mouse, rat, monkey and human brain, a picture emerges in which the basal forebrain (BF) cholinergic system targets the neocortex with much more spatial and temporal detail than previously considered. Fast cholinergic synapses acting on a millisecond time scale are abundant in the mammalian cerebral cortex, and provide BF cholinergic neurons with the possibility to rapidly alter information flow in cortical microcircuits. Finally, recent studies have outlined novel mechanisms of how cholinergic projections from the BF affect synaptic strength in several brain areas of the rodent brain, with behavioral consequences. This review highlights these exciting developments and discusses how these findings translate to human brain circuitries.

Keywords: acetylcholine; basal forebrain; interneurons; microcircuits; neocortex; pyramidal neuron; synaptic plasticity; synaptic transmission.

Figure 1

Cholinergic responses in adult human neocortex are cell type and lamina-dependent. (A) Left: example reconstruction of biocytin-labeled human L2/3 pyramidal neuron. Right: No change in membrane potential occurred in response to a local application (puff) of 1 mM Acetylcholine (Ach; green bar, 30 s). (B) Left: example reconstruction of biocytin-labeled human L6 pyramidal neuron. Right: examples of no change in membrane potential (top) and a depolarization (bottom) in response to a local application of 1 mM ACh (green bar, 30 s). (C) Examples of biocytin-labeled human interneurons, with action potential firing profiles in response to step current injections and voltage or current responses to local application of 1 mM ACh (green bar, 30 s). Gray traces were recorded in the presence of nicotinic acetylcholine receptor (nAChR) blockers mecamylamine (MEC, middle traces, 1 μM) or dihydro-b-erythroidine hydrobromide (DHβE, bottom traces, 1 μM). (D) Overview of functional nicotinic AChR expression in pyramidal neurons and the predicted expression in interneurons in different lamina of the human temporal cortex. Data figures are representing edited versions of previously published findings (Alkondon et al., ; Verhoog et al., 2016).

Figure 2

In adult human neocortex, ACh alters long-term synaptic plasticity of glutamatergic synapses in opposite directions in superficial and deep layers. Top, left: In adult human neocortical L2/3 pyramidal neurons in control conditions (open gray square) and experiments where ACh was present in the bath during long-term potentiation induction (pre- and postsynaptic activity pairing, open green circle). Top, middle: top traces: example EPSP waveforms recorded during baseline (light color) and 20–25 min. after pairing (dark color), for tLTP experiments with and without ACh present in bath during pairing. Horizontal scale bar: 30 ms; vertical scaling as below. Bottom traces: membrane potential change over course of pairing period (gray shading) relative to baseline for experiments where ACh was washed-in during pairing. Scale bars, 3 mV, 2 min. Top, right: summary bar chart showing change in EPSP slope of control LTP and ACh LTP experiments in human L2/3 neurons. Bottom, as in top figure, for nAChR-bearing human L6 pyramidal neurons. Note that in contrast to L2/3, in L6 long-term potentiation of human glutamatergic synpases is increased by ACh (*p ≤ 0.05). Figure is modified from Verhoog et al. (2016), no permission required.