Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

Abstract

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated pools of neurons that may modulate specific cortical areas.

Barrel cortex VIP/ChAT interneurons suppress sensory responses in vivo

“…Fig 5F shows the response of a neuron in the 40 ms following whisker stimulation (trials are sorted by the latency to the first evoked spike). We found that the average latency in the Off trials was shorter than the average latency in the On trials, in which the VChIs were optogenetically stimulated (Latency On 18.7 ± 1.1 ms, Latency Off : 16.9 ± 0.8 ms; paired t test, t [17] = 2.44, p = 0.03). This longer average latency provides additional evidence for the inhibitory effect of VChIs on the sensory response.…”

“…The scatter plot in Fig 5D compares the average PSTH peak amplitude for the intermediate whisker deflections (0.6, 1.0, and 1.4 mm) between the light Off and On conditions. For this range of whisker deflections, there is a significant reduction in the peak PSTH response (Off: 17 ± 3 spikes/s, On: 14 ± 3 spikes/s; n = 18, paired t test, t [17] = 4.3, p = 0.0005). It has been reported that spontaneous whisking can cause ACh release in the cortex from BF cholinergic projections as well as activate local VIP + interneurons [16,38,39].…”

“…We pooled together all intermediate whisker deflections for each group and normalized the evoked rate in each condition by the mean evoked response of the cell across conditions (Fig 5E). We found a significant main effect of whisking and of optogenetics with no effect of interaction (On LW : 1.11 ± 0.05, Off LW : 1.35 ± 0.06, On HW : 0.65 ± 0.07, Off HW : 0.89 ± 0.06; two-way repeated-measures ANOVA; a main effect of optogenetics F[1,17] = 20.82, p = 0.0003, η 2 G = 0.17; a main effect of whisking F[1,17] = 18.36, p = 0.0005, η 2 G = 0.43; no optogenetics × whisking effect of interaction F [1,17] = 0.002, p = 0.96, η 2 G = 1.5 × 10 −5 ). Finally, we measured the latency to the first spike following whisker stimulation.…”

“…ACh modulates neuronal biophysical properties such as synaptic release probability and gain of potassium ion channels [12][13][14][15][16][17][18][19][20]. ACh also affects high-level cognitive functions such as attention and memory [21][22][23][24][25][26][27].…”

Cell-specific modulation of plasticity and cortical state by cholinergic inputs to the visual cortex

“…For example, VIP neurons inhibit PV neurons in the superficial layers of mouse auditory cortex (Letzkus et al, 2011; Pi et al, 2013), whereas such inhibition is not clearly observed in the visual cortex (Karnani et al, 2016; Pfeffer et al, 2013). Furthermore, cortical projections of BF are topographically organized (Zaborszky et al, 2015) and cholinergic modulation can be cortical area specific (Chaves-Coira et al, 2016; Golmayo et al, 2003; Rasmusson et al, 2007). Thus, cholinergic modulation can be task specific and also different tasks with varied cholinergic load could activate distinct cortical circuits (Chen et al, 2015).…”