Activity-dependent regulation of basal forebrain cholinergic neurons by striatal spiny projection neurons

The basal forebrain cholinergic neurons (BFCNs) in substantia innominata (SI) and nucleus basalis magnocellularis (nBM) provide dense innervation to multiple cortical areas, shaping cognition, attention, and the sleep-wake cycle. However, the afferent connectome controlling the spiking of BFCNs is poorly characterized. Although biased toward the nearby ventral striatum, monosynaptic rabies virus mapping revealed that spiny projection neurons (SPNs) throughout the striatum innervated BFCNs in the SI/nBM. Roughly 1-5% of SPNs were retrogradely labeled, with both D1 dopamine receptor-expressing SPNs (D1R-SPNs) and D2 dopamine receptor-expressing SPNs (D2R-SPNs) making similar contributions to the total. Nevertheless, optogenetic activation of D1R-SPN axons in ex vivo brain slices from male mice evoked significantly more robust responses in BFCNs than did activation of D2R-SPNs. Interestingly, although the response to transient D1R-SPN stimulation was dominated by GABAergic inhibition of ongoing BFCN spiking, more sustained stimulation led to a significant elevation in BFCN spiking that outlasted the stimulation. This persistent excitation was attributable to engagement of tachykinin 1 receptors (NK1Rs) and acid-sensing cation channels (ASICs). These studies demonstrate that a spatially distributed population of D1R-SPNs exerts significant regulation of BFCN activity, which could play an important role in arousal, cognition, and sleep.<b>Significance statement</b> Basal forebrain cholinergic neurons (BFCNs) are the principal source of the cortical cholinergic innervation critical to shaping cognition, sleep and arousal. Although striatal spiny projection neurons (SPNs) constitute a significant component of the BFCN connectome, which SPN subtype contributes to this innervation, and their functional role is unclear. Here, we show that both D1 dopamine receptor (D1R)-expressing and D2 dopamine receptor (D2R)-expressing SPNs innervate BFCNs. However, optogenetic stimulation of D1R-SPNs resulted in a more robust GABAergic suppression of baseline BFCN activity. Furthermore, burst stimulation of D1R-SPNs resulted in a prolonged excitation of BFCNs attributable to activation of tachykinin receptors and acid-sensing ion channels. These studies point to a novel role for SPNs in the regulation of cognition, sleep, and arousal.