Research reportDifferential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist
Introduction
Cells of the auditory cortex (AC) receive sensory input from thalamic relay cells of the medial geniculate nucleus (MG; extrinsic inputs), and from other cells within the cortex (intrinsic inputs) which themselves can receive either direct or indirect MG input ( [8], [45], [46], [55], [56], [57], [60], [72], [75] and reviewed in [73], [74]). These two sources of input combine to produce sensory evoked responses observed in AC.
The AC also receives non-sensory inputs that modulate evoked responses (see reviews by [34], [35]). Prominent among these is the projection from the cholinergic basal forebrain, the major source of ACh to the AC (reviewed by [40], [62]). The cholinergic system exerts powerful effects on sensory cortex, influencing cellular excitability, cortical state, and receptive field plasticity [5], [11], [14], [22], [29], [36], [38], [41], [44], [50]. In particular, application of cholinergic agonists or stimulation of the basal forebrain can profoundly modulate cortical EPSPs in sensory cortex both in vivo and in vitro [3], [6], [11], [19], [31], [42], [51].
While the influence of ACh on sensory cortical responses is undisputed, little is known regarding the degree to which it regulates transmission coming from extrinsic (thalamocortical) vs. intrinsic (intracortical) sources. This may be surprising considering the importance of such knowledge for understanding cholinergic regulation of sensation and perception. However, the acquisition of relevant data has been hampered by several factors, including the difficulty in conducting appropriate experiments in vivo and the limited availability of in vitro preparations with intact thalamocortical connections [1], [49]. In one in vitro study which directly tests this issue, Gil et al. [19] utilized a somatosensory thalamocortical slice to demonstrate that activation of muscarinic ACh receptors suppressed intracortical and thalamocortical EPSPs similarly. In contrast to these findings, muscarinic actions in hippocampus and piriform cortex result in a strong suppressive effect on intracortical synapses with little effect on responses to extrinsic inputs [24], [26]. An important question that emerges from these studies is whether the contrasting findings reflect functional distinctions between neocortex [19] vs. archicortex/paleocortex [24], [26], or other, possibly methodological, differences. Indirect evidence addressing this issue comes from the recent work of Kimura et al. [30]. They found that ACh suppressed responses to white matter stimulation in upper and lower layers of visual cortex more than in the thalamo-recipient middle layers. The authors propose that muscarinic suppression of intracortical synapses is stronger than that of thalamocortical synapses. This would suggest that the distinction between neocortex and archicortex/paleocortex (hypothesized above) may not be valid.
To address this issue, we have utilized a slice preparation of the AC that, like the somatosensory thalamocortical slice used by Gil et al. [19], preserves both extrinsic inputs from the thalamus and intrinsic, long-range intracortical connections [43]. With this slice, we directly compare cholinergic modulation of thalamocortical and intracortical synaptic transmission. Portions of this work have appeared in abstract form [28].
Section snippets
Preparation of slices
All procedures followed the University of California, Irvine, animal use regulation. Slices were taken from 15 to 43-day-old FVB mice and maintained in vitro (described by Metherate and Cruikshank [43]). Following decapitation under halothane anesthesia, brains were rapidly removed (<60 s) and placed in 0–4°C artificial cerebrospinal fluid (ACSF) containing (in mM): NaCl 125, KCl 2.5, KH2PO4 1.25, NaHCO3 25, MgSO4 1.2, CaCl2 2, dextrose 10; bubbled with 95% O2/5% CO2. Auditory thalamocortical
Results
The results are divided into two sets of experiments. The initial experiments were designed to separately activate extrinsic (subcortical) and intrinsic (intracortical) inputs leading to AC. We placed one stimulating electrode subcortically, within the downstream part of the auditory thalamocortical pathway, and a second stimulating electrode within the middle layers of the cortex lateral to the recording electrode (Fig. 1A). Recordings were made in layer IV of AC at the site of the maximal
Discussion
We have examined cholinergic modulation of responses evoked by stimulation of extrinsic (thalamocortical) and intrinsic (intracortical) inputs to auditory cortex. For both pathways, muscarinic modulation suppressed long-duration polysynaptic responses more strongly than it suppressed monosynaptic potentials. Further, intrinsic monosynaptic responses were suppressed significantly more than were extrinsic monosynaptic responses. These differential findings have important implications for
Acknowledgements
Thanks to Dr. V. B. Aramakis for helpful discussions and comments on the manuscript. This work was supported by the NSF (IBN 9510904), NIDCD (DC02967), University of California Tobacco-Related Disease Research Program (8RT-0059) and an NIMH training grant (MH14599).
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2021, NeuroscienceCitation Excerpt :ACh may act via mAChRs or nAChRs (or both) to modulate short-term synaptic plasticity by means of presynaptic regulation of transmitter release. The cholinergic modulation of intracortical synaptic transmission was found in different cortical layers, resulting in an increase of the ‘signal-to-noise ratio (SNR)’ in cortical networks thereby increasing the sensitivity of cortical neurons to external stimuli (Hsieh et al., 2000; Oldford and Castro-Alamancos, 2003). Both subtypes of Gi protein-coupled mAChRs, M2 and M4-type receptors, are expressed at presynaptic terminals of both rodent and human neocortical neurons (Levey et al., 1991; for reviews see Thiele, 2013; Obermayer et al., 2017).
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These authors contributed equally to the work.