A functional logic for neurotransmitter co-release in the cholinergic forebrain pathway

Abstract

The forebrain cholinergic system has recently been shown to co-release both acetylcholine and GABA. We have discovered that such co-release by cholinergic inputs to the claustrum differentially affects neurons that project to cortical versus subcortical targets. The resulting changes in neuronal gain toggles network efficiency and discriminability of output between two different projection subcircuits. Our results provide a potential logic for neurotransmitter co-release in cholinergic systems.

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

“…The excitatory responses to cholinergic input observed by Nair et al (2021) were monosynaptic and mediated by nAChRs, in line with the high expression of nAChRs in the claustrum noted above (Winzer-Serhan and Leslie, 2005). Nair et al (2021) observed that inhibitory cholinergic input received by cortexprojecting claustral neurons was also monosynaptic but was produced by a surprising co-release of ACh and GABA by the basal forebrain. Thus, depending on their projection targets, claustrum neurons receive opposing excitatory and inhibitory input from the basal forebrain.…”

“…Optogenetic activation of cholinergic axons indicated that claustral neurons receive cholinergic input in a cell-type specific manner: cortex-projecting claustrum neurons were primarily inhibited, while claustrum neurons projecting to subcortical structures (including thalamus and habenula) and vasointestinal peptide (VIP) expressing interneurons in the claustrum were excited. The excitation of VIP interneurons in the claustrum mirrors observations in the cortex (Fu et al, 2014), with the notable exception that cholinergic input did not excite somatostatin (SST) expressing interneurons or parvalbumin (PV) expressing interneurons in the claustrum (Nair et al, 2021) but does excite these interneurons in the cortex.…”

“…The role of endogenous cholinergic signaling has recently been clarified in a study by our group that used optogenetics to probe cholinergic modulation in mouse claustrum brain slices (Nair et al, 2021). Optogenetic activation of cholinergic axons indicated that claustral neurons receive cholinergic input in a cell-type specific manner: cortex-projecting claustrum neurons were primarily inhibited, while claustrum neurons projecting to subcortical structures (including thalamus and habenula) and vasointestinal peptide (VIP) expressing interneurons in the claustrum were excited.…”

“…Cholinergic modulation is known to alter the gain of cortical neurons, which is defined as a change in neuronal input-output properties (Silver, 2010;Polack et al, 2013;Dasilva et al, 2019). Similarly, cholinergic input also affects the gain of claustral neurons (Nair et al, 2021). The opposing excitatory and inhibitory effects observed on different projection neuron subtypes in the claustrum translates into opposing effects on the gain of these neurons: cholinergic input decreases the gain of cortex-projecting claustral neurons, while increasing the gain for subcortex-projecting neurons and VIP interneurons.…”

“…How might cholinergic modulation contribute to the claustrum's role in attention? We propose that cholinergic modulation is a permissive agent: in attentive states, when cholinergic input is high, the observations of Nair et al (2021) predicts that information flow will be biased towards the cortexprojecting claustrum population, allowing this projection to inhibit the cortex. In non-attentive states, when cholinergic levels are low, the claustrum will be unable to inhibit cortical targets as information flow is toggled towards the subcortex-projecting claustrum neurons (Nair et al, 2021).…”