Previous studies have shown that local application of ACh or AChR agonists can affect the firing rate and receptive field properties of visual cortical neurons31–34,42
, although the observed changes were diverse across neurons and sometimes inconsistent between studies. In this study, by directly activating the source of cholinergic projections to the entire cortex, we have demonstrated two robust effects of NB activation on visual coding, mediated by distinct mechanisms. Furthermore, we found that both the decorrelation and increased reliability contribute to improved discriminability of the neuronal responses to different natural stimuli, a hallmark of enhanced visual coding.
In rat neocortex, nAChRs are expressed primarily in layer 4 (and to a lesser extent in layer 5) in both cortical neurons and thalamic terminals, whereas mAChRs (M1
) are expressed throughout the cortex, with different subtypes preferentially expressed in different layers43
. Thalamocortical input is shown to be enhanced by nAChR activation, while excitatory intracortical synaptic activity can be suppressed by mAChRs24,25
. The mAChR-mediated hyperpolarization of fast-spiking interneurons may also suppress thalamocortical feedforward inhibition23,26
. Based on these effects at the cellular level, a common view is that ACh enhances thalamocortical inputs but suppresses intracortical interactions24–27,44
. Our finding that NB-induced decorrelation between neurons requires local activation of mAChRs is consistent with this notion. However, while previous studies showed that activation of cortical AChRs increases the amplitude of thalamocortical input30,45
, we found that the improved response reliability was not reduced by local block of either mAChRs or nAChRs in the cortex (). This indicates that the NB-induced improvement in response reliability is not due primarily to the increased amplitude of thalamocortical input, but involves changes in the sensory signals earlier in the processing pathway. Our observation is also consistent with a recent finding that iontophoretic application of ACh in the visual cortex does not reduce the trial-to-trial variability of the neuronal responses34
Our experiments showed that NB stimulation increases the response reliability and decreases the burst-tonic ratio of LGN neurons (). Since NB does not project directly to the LGN, these effects must be mediated by indirect pathway(s) (through either cholinergic or GABAergic projections from the NB46,47
), such as NB → cortex → LGN, NB → thalamic reticular nucleus → LGN22,46
, or NB → brainstem reticular formation → LGN22,46
(although the lack of effect of atropine and mecamylamine injected into the LGN argues against the involvement of cholinergic projection from the reticular formation). These pathways could depolarize LGN neurons29
and inactivate T-type Ca2+
, thereby increasing the response reliability and reducing the burst-tonic ratio. The changes in the LGN activity are likely to improve the fidelity of the sensory input to the cortex and thus explain the NB-induced increase in cortical response reliability (). Such distributed improvement of neuronal responses along the sensory pathway could contribute to NB-induced enhancement of sensory cortical plasticity9,11
, in addition to the local cholinergic effects in the cortex10
. An intrinsic limitation of the extracellular stimulation technique is that it is difficult to distinguish the contributions of cholinergic and GABAergic NB neurons and to rule out the potential activation of axons originating from other brain regions passing through the NB. Future studies using optogenetic techniques48
to activate specific cell types may help to determine the role of each cell type in regulating sensory coding along the thalamocortical pathway.
The activity of cholinergic neurons in the basal forebrain undergoes striking changes from the sleep to awake states12,13,15
. Recent studies showed that even in the awake state NB activity varies in a task-dependent manner14,15
, and it may be involved in regulating sensory processing under different forms of uncertainty49
. Since NB receives input from both subcortical regions and prefrontal cortex7
, it may act as a way station for both bottom-up and top-down signals to regulate sensory coding in a behaviorally-relevant manner. Our finding that NB activation can rapidly improve visual representation in the cortex offers a mechanism by which perceptual abilities are enhanced during wakefulness, arousal, and attention.