Pyramidal tract neurons drive amplification of excitatory inputs to striatum through cholinergic interneurons

Abstract

Corticostriatal connectivity is central for many cognitive and motor processes, such as reinforcement or action initiation and invigoration. The cortical input to the striatum arises from two main cortical populations: intratelencephalic (IT) and pyramidal tract (PT) neurons. We report a previously unknown excitatory circuit, supported by a polysynaptic motif from PT neurons to cholinergic interneurons (ChIs) to glutamate-releasing axons, which runs in parallel to the canonical monosynaptic corticostriatal connection. This motif conveys a delayed second phase of excitation to striatal spiny projection neurons, through an acetylcholine-dependent glutamate release mechanism mediated by α4-containing nicotinic receptors, resulting in biphasic corticostriatal signals. These biphasic signals are a hallmark of PT, but not IT, corticostriatal inputs, due to a stronger relative input from PT neurons to ChIs. These results describe a previously unidentified circuit mechanism by which PT activity amplifies excitatory inputs to the striatum, with potential implications for behavior, plasticity, and learning.

Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington’s disease model mice

“…Oxo-M had no effect on oEPSCs evoked by PT stimulation in either dSPNs or iSPNs (Figs. 4b, c, S4a), in agreement with recent work 22 .…”

“…This clearly complicates the interpretation of these previous results. For example, electrical stimulation might have led to preferential activation of PT axons, which are larger and have a lower threshold for electrical stimulation 18 ; as glutamate release by PT terminals is enhanced by ACh release and nAChR activation 22 rather than being inhibited by mAChRs, their preferential recruitment in HD models-where ACh release is reducedcould have led to the appearance of impaired corticostriatal connectivity.…”

“…Distinguishing between them could prove to be critical to understanding striatal HD pathophysiology, particularly in light two additional observations. The release of glutamate at corticostriatal axospinous synapses is controlled by presynaptic G-protein coupled receptors (GPCRs) and by ionotropic nicotinic ACh receptors (nAChRs) [21][22][23][24] . One of the most prominent of the GPCRs at these terminals is the inhibitory G i/o -coupled muscarinic acetylcholine receptor (mAChR) that-like the nAChR-is activated by acetylcholine (ACh) release by giant, aspiny striatal cholinergic interneurons (ChIs) 21,24,25 .…”

“…One of the most prominent of the GPCRs at these terminals is the inhibitory G i/o -coupled muscarinic acetylcholine receptor (mAChR) that-like the nAChR-is activated by acetylcholine (ACh) release by giant, aspiny striatal cholinergic interneurons (ChIs) 21,24,25 . Interestingly, activation of nAChRs facilitate glutamate release selectively at PT synapses 22 , raising the possibility that the prominent mAChR-mediated suppression of corticostriatal glutamate release seen with electrical stimulation of axons occurs only at IT synapses. Added motivation for pursuing this connection comes from the observation that, although they are not lost in HD, ChIs are functionally compromised [26][27][28][29] , suggesting that striatal pathophysiology in HD stems in part from an imbalance in IT and PT control of SPNs.…”

Ongoing movement controls sensory integration in the dorsolateral striatum

“…Another possibility is that DA depletion has different impact on the intratelencephalic (IT) and pyramidal tract (PT) pathways 66 , thus differentially affecting ipsi- and contralateral corticostriatal inputs as well as cortico-callosal projections 67 . The changes in the respective pathways could be directly on the axons of cortical projection neurons but could also be mediated indirectly via intrastriatal mechanisms such as cholinergic interneurons that were shown to be activated primarily by PT inputs 24 , 68 and regulate corticostriatal transmission 69 . The mechanisms underlying the changes in laterality coding are, however, not completely clear and should be further investigated in future studies.…”