Acetylcholine dynamically controls spatial integration in marmoset primary visual cortex

Abstract

Recent in vitro studies have shown that acetylcholine (ACh) selectively reduces the efficacy of lateral cortical connections via a muscarinic mechanism, while boosting the efficacy of thalamocortical/feed-forward connections via a nicotinic mechanism. This suggests that high levels of ACh should reduce center-surround interactions of neurons in primary visual cortex, making cells more reliant on feed-forward information. In line with this hypothesis, we show that local iontophoretic application of ACh in primate primary visual cortex reduced the extent of spatial integration, assessed by recording a neurons' length tuning. When ACh was externally applied, neurons' preferred length shifted toward shorter bars, showing reduced impact of the extra-classical receptive field. We fitted a difference and a ratio of Gaussian model to these data to determine the underlying mechanisms of this dynamic change of spatial integration. These models assume overlapping summation and suppression areas with different widths and gains to be responsible for spatial integration and size tuning. ACh significantly reduced the extent of the summation area, but had no significant effect on the extent of the suppression area. In line with previous studies, we also show that applying ACh enhanced the response in the majority of cells, especially in the later (sustained) part of the response. These findings are similar to effects of attention on neuronal activity. The natural release of ACh is strongly linked with states of arousal and attention. Our results may therefore be relevant to the neurobiological mechanism of attention.

FIG. 1

Single cell examples. Mean stimulus driven response to seven stimuli of varying length in the presence (black) and absence (gray) of acetylcholine (ACh). Smooth lines show fitted difference of Gaussians (DOG) models. Vertical arrows mark preferred length, taken as the peak of the fitted curve. Preferred length was shortened with ACh present. Error bars show SE. Histograms at the base of graphs show distribution of preferred length determined by the bootstrap method with ACh present (black histogram) and absent (gray histogram). x-axis: bar length in multiples of classical receptive field (minimum response field mapping).

FIG. 2

Preferred length and fitting parameters extracted from DOG (top row) and the ratio of Gaussian model (bottom row). A: preferred lengths of neurons (n = 66 cells) with ACH absent (x-axes) and ACh present (y-axes). Cells that shifted their tuning toward shorter bars during ACh application appear below the diagonal. B: spatial summation area with ACh absent and present. Summation area decreased in the presence of ACh. C: suppression area with ACh absent and present. Width of suppression area was not affected by ACh application D: gain of summation area with ACh absent and present. E: gain of suppression area with ACh absent and present. Black dots, neurons for which the parameter of interest changed significantly as a function of ACh application; open squares, neurons for which no significant change was found (bootstrap method); symbols (dots, squares), horizontal, and vertical bars, median and 25-75 CIs for the parameter of interest (bootstrap method).

FIG. 3

Population activity as a function of bar length and ACh application. Population activity for cells facilitated with and without spontaneous activity subtracted (left 2 columns) and suppressed (right columns) by ACh with ACh absent (solid gray line) and ACh present (dashed black line) for bar length 0.2-12.8 times the minimum response field (mRF) diameter (top to bottom). Neurons facilitated by ACh showed increased activity from response onset particularly when bars were shorter than the neuron’s mRF diameter (0.2 and 0.4 mRF diam), but the largest differences occurred during later response periods for all bar lengths. Effect of ACh on suppressed neurons was strongest when bars larger than the mRF were presented.

FIG. 4

Preferred length and summation area as a function of time for cells facilitated by ACh and cells suppressed by ACh. Preferred length and summation area with ACh absent (gray line, gray area shows SE) and present (dashed black line, dashed flanking lines show SE) for cells facilitated (left) and suppressed (right) by ACh. With ACh present, preferred length and summation area were reduced from ∼150-200 ms after stimulus onset in cells facilitated by ACh, whereas this difference occurred somewhat later (230-280 ms) for cells suppressed by ACh, and it did not become significant until ∼320 ms after response onset in the latter cell group. Histograms at the base show time-resolved P values (1/P value) of differences between the ACh present/absent condition.

FIG. 5

Strength of sustained response as a function of ACh. Tonic index for cells measured with bar length ranging from 0.2 to 12.8 times mRF (top) and measured with bar length ranging from 0.5 to 5 times mRF (bottom) for cells facilitated by ACh (left) and cells suppressed by ACh (right). Sustained response was on average increased in the presence of ACh (black dashed curves and error bars) compared with its absence (gray solid curves and error bars). Error bars are SE.