Basal forebrain activation controls contrast sensitivity in primary visual cortex
- Anwesha Bhattacharyya†1, 2,
- Julia Veit†1, 2,
- Robert Kretz1,
- Igor Bondar3 and
- Gregor Rainer1, 2Email author
© Bhattacharyya et al.; licensee BioMed Central Ltd. 2013
Received: 15 January 2013
Accepted: 6 May 2013
Published: 16 May 2013
The basal forebrain (BF) regulates cortical activity by the action of cholinergic projections to the cortex. At the same time, it also sends substantial GABAergic projections to both cortex and thalamus, whose functional role has received far less attention. We used deep brain stimulation (DBS) in the BF, which is thought to activate both types of projections, to investigate the impact of BF activation on V1 neural activity.
BF stimulation robustly increased V1 single and multi-unit activity, led to moderate decreases in orientation selectivity and a remarkable increase in contrast sensitivity as demonstrated by a reduced semi-saturation contrast. The spontaneous V1 local field potential often exhibited spectral peaks centered at 40 and 70 Hz as well as reliably showed a broad γ-band (30-90 Hz) increase following BF stimulation, whereas effects in a low frequency band (1-10 Hz) were less consistent. The broad γ-band, rather than low frequency activity or spectral peaks was the best predictor of both the firing rate increase and contrast sensitivity increase of V1 unit activity.
We conclude that BF activation has a strong influence on contrast sensitivity in V1. We suggest that, in addition to cholinergic modulation, the BF GABAergic projections play a crucial role in the impact of BF DBS on cortical activity.
KeywordsGamma oscillations Orientation tuning Cholinergic
Cholinergic neuromodulation is mediated by several basal forebrain (BF) structures including the nucleus basalis of Meynert (NBM), which send cholinergic projections to the cortex [1, 2]. These cholinergic projections play an important role in various cognitive functions including learning, memory formation and attention [3–5]. Behaviorally, immunotoxic lesions of the cholinergic system have profound effects on learning [6–9], consistent with a large body of evidence linking the blockade of the muscarinic acetylcholine receptors (mAChR), as well as to a lesser extent the nicotinic acetylcholine receptors (nAChR), to impairments in memory formation as well as stimulus discrimination and attention [10, 11]. Behavioral performance with novel stimuli appears to be particularly affected by mAChR blockade [12, 13]. On the other hand, application of cholinergic agonists can have beneficial effects on behavioral performance. For example, nAChR agonist application enhances the detection performance for low contrast stimuli  and administration of the Acetylcholine-esterase inhibitor physostigmine enhances attentional performance [15, 16]. These behavioral effects are thought to be mediated by the impact of cholinergic neuromodulation on cortical information processing. Thus, pairing cholinergic activation with sensory stimulation boosts subsequent responses to sensory stimuli in both auditory and visual cortex [17–19] as well as promoting cortical map plasticity [20, 21]. Consistent with this, it has been shown that mAChRs play an important role in synaptic plasticity [22–24].
Effects of cholinergic neuromodulation on sensory processing have been extensively investigated using iontophoretic drug application, with much effort having been directed at studies of the primary visual cortex (V1). Early studies have described response increases following the application of cholinergic agonists [25–27] and more recent work has begun to link particular aspects of cholinergic neuromodulation to specific receptor types and cortical laminae [28–31]. By comparison to this pharmacological work, there are relatively few studies examining how cortical processing is affected by electrical BF stimulation, which evokes endogenous Acetylcholine (ACh) release in the cortex [32–34]. This is somewhat surprising given that BF stimulation is currently being tested for clinical use in patients suffering from brain disorders linked to cholinergic dysfunction such as Alzheimer’s disease and Lewy body dementia [35, 36]. We therefore aimed to investigate the effects of BF stimulation on sensory processing in the visual cortex, and link the observed effects to our previous results of selective nAChR and mAChR stimulation . An important pertinent aspect is that the BF also sends substantial GABAergic projections to both cortex and thalamic structures [38, 39], providing additional routes by which the BF can exert an influence on cortical processing. In our analysis of BF stimulation effects, we focused on spectral changes in the V1 local field potential (LFP) in the absence of visual stimulation, and on the contrast sensitivity [40, 41] and orientation selectivity [42, 43] of V1 single (SUA) and multi-unit activity (MUA) in response to drifting grating stimuli.
We investigated how BF stimulation affected sensory representations by examining parameters related to the contrast response and orientation selectivity of V1 units. We observed strong increases in firing rates, a pronounced increase in contrast sensitivity and decreases in orientation selectivity.
Since the BF, where we stimulated in the present study, contains a large population of cholinergic cortical projection neurons [2, 45], the results of BF stimulation thus might be thought to have been predictable based on the results of pharmacological application of ACh or specific agonists of nAChR and mAChR types in V1. Iontophoretic ACh application has both excitatory and inhibitory effects on unit activity, with most studies reporting about twice as many increased compared to suppressed units [25, 27, 31, 46, 47], but see . Selective stimulation of the nAChR has been shown to elicit facilitation in a great majority of units, particularly in the granular input layer of cortex [28, 37]. Similarly, mAChR stimulation also tends to elicit facilitation, although these effects appear to occur in all cortical layers [27, 31, 46]. Comparing our present findings to our previous data on iontophoretic cholinergic drug application in tree shrew V1 and taking the change in baseline-subtracted peak firing rate (ΔRmax) as a measure of effect size for facilitation, we observed average values of +25%, +45% and +130% for mAChR, nAChR and BF stimulation respectively. The ΔRmax value following BF stimulation is thus greater than the sum of the increases due to the two cholinergic receptor types, although release profiles following iontophoretic drug application and BF stimulation may differ, complicating direct comparisons. Nevertheless, it seems that cholinergic BF projections to the cortex are unlikely to be the only mechanism involved in the increase of cortical firing rates. A stronger case for non-cholinergic contributions following BF stimulation can be made concerning contrast sensitivity changes. To our knowledge, our findings in fact represent the first demonstration of a physiological intervention that reduces C50 values in the visual cortex and thus enhances the ability of neurons to detect low contrast stimuli. Accordingly, C50 values are unaffected by ACh application [29, 31] nAChR [28, 37] or mAChR stimulation [31, 37], GABA-A blockade  or alteration of parvalbumin-containing GABAergic interneuron activity . Furthermore, it has been shown that C50 values in the LGN are unaffected by both alertness levels and isoflurane anesthesia [50, 51]. The lack of V1 C50 modulations in response to cholinergic pharmacological agents suggests that reductions in C50 values in response to BF stimulation cannot be accounted for by BF cholinergic projections alone.
Cholinergic activation has been shown to have relatively weak effects on selectivity to stimulus features such as orientation and direction in V1, with studies reporting moderate decreases [27, 46, 47] as well as increases [25, 26]. Our own previous results in tree shrew V1 have suggested slight increases and decreases of orientation selectivity mediated by mAChRs and nAChRs respectively . Generally consistent with previous findings, we report here unchanged TW, increased TH and decreased OSI values in response to BF stimulation. The relatively large decrease in OSI values – despite the increase in tuning height and unchanged width – is a result of the large general increase in V1 firing rates, even for non-preferred orientations.
Increase in broad γ-band activity in the cortex has been linked to BF activation [66–70], and – in addition to reductions in low frequency activity – is used as a relevant aspect of the cortical spectrogram for the placement of BF stimulation electrodes [33, 67]. Here, we found that γ-band effects could take the form of broad-band increases, as well as displaying peaks with center frequencies around 40 Hz and 70 Hz. Notably, dual peaks with similar center frequencies have been previously observed in visual cortical slice preparations during mAChR stimulation [71, 72]. Similarly, it has been shown that γ-band oscillations with a somewhat lower peak frequency of 26 Hz can be evoked in the visual cortex in vivo by application of the cholinergic agonist Carbachol . This suggests that the γ-band peaks we observed in visual cortex following BF stimulation are likely to be a result of cholinergic BF projections to the cortex that target mAChRs, which in turn up-regulate perisomatic GABAergic inhibition. Interestingly, we were able to elicit γ-band peaks only at medial BF sites within and close to the NB, whereas stimulation at more lateral BF sites did not elicit any peaks while nevertheless evoking increased broad γ-band activity. We speculate that medial stimulation sites might thus be more suitable for activating BF cholinergic projections to the cortex, possibly by targeting fibers of passage that initially take a medial course from the NBM, before projecting posteriorly . Our correlation analyses suggest that the γ-band peaks do not predict firing rate (ΔRmax) or contrast sensitivity (ΔC50) increases following BF stimulation. Instead, it is the broad γ-band activity which is correlated with both ΔRmax and ΔC50 values, suggesting that the overall strength of γ-power, rather than the appearance of specific peaks is related to the main effects on V1 unit activity. Generally, γ-oscillations are thought to be generated by the interplay between local excitatory and inhibitory coupled networks . It is therefore likely that, in addition to the cholinergic BF projections to the cortex, the two GABAergic pathways originating from the BF (see Figure 7) also contribute to the increase of γ-band activity. This could be accomplished by shifting the balance between excitation and inhibition in cortex through an up-regulation of thalamo-cortical excitatory drive and the reduction of GABAergic inhibition onto cortical pyramidal cells, through the BF GABAergic projections to the reticular nucleus and cortex respectively. An involvement of GABAergic cortical projection pathways is consistent with modeling work suggesting that reduced drive to a set of cortical interneurons leads to γ-oscillations in a coupled network of excitatory and inhibitory neurons . At the same time, the GABAergic projection to the reticular nucleus could also play a role, consistent with the recent demonstration that coupled inhibitory networks in conjunction with long range excitation can generate broad γ-band activity without ostensible spectral peaks .
In summary, our major finding is a strong increase in the contrast sensitivity of V1 neurons as well as a large increase in neural responsiveness following BF DBS. Converging evidence suggests that these effects are unlikely to be due to the action of cholinergic mechanisms alone. We suggest that the action of GABAergic BF projection pathways is a candidate mechanism that could account for the observed findings, by causing disinhibition of V1 pyramidal neurons. This disinhibition may also contribute to the reduced stimulus selectivity we observed following BF stimulation, consistent with previous findings showing reduced stimulus selectivity in V1 as well as inferior temporal cortex following GABA receptor blockade [48, 78]. Given that these effects are likely to be detrimental for visual discrimination performance , it is important to carefully consider the co-activation of GABAergic, in addition to cholinergic BF projections in clinical applications of BF stimulation.
All experiments were approved by the “Tierversuchskommission des Kantons Fribourg” and were in full compliance with applicable Swiss as well as European Union directives.
Experiments were performed on six adult tree shrews (Tupaia belangeri) aged 3–9 years. Animals were prepared as described previously . Briefly, experiments were carried out in anesthetized and paralyzed animals (0.5%-1.5% Isoflurane in Oxycarbon (95%O2, 5%CO2), Pancuroniumbromide i.p.) that were artificially respirated at 100 strokes per minute.
Stimulation electrodes consisted of two Teflon insulated Platinum/Iridium Pt90/Ir10 wires (0.05mm diameter), twisted together and placed inside a Silica guide tube (250 μm ID, 350 μm OD). Impedances ranged from 500kΩ to 1.2MΩ. The stimulation stereotrode was advanced vertically downwards at the AP-ML coordinates of the NBM using a hydraulic microdrive until a depth of about 7000 μm was reached. We electrically stimulated at this position and observed the changes in the local field potential. If the V1 LFP did not show the expected frequency changes – particularly a γ-band increase – after stimulation, we advanced the stimulation electrode in approximately 200 μm steps further until we observed the expected V1 LFP spectral signature, at which point we left the stimulation stereotrode in place for the rest of the experiment. We then recorded neural activity from different depths in V1, conducting at each site first a “BF stim only” protocol to quantify the spectral changes in the spontaneous LFP, and then a “BF stim grating” protocol with and without BF DBS in separate blocks.
Tetrodes were fabricated by twisting together four 12.7 μm-diameter nickel–chromium wires (RO-800; Kanthal Precision Technology) and the impedances were reduced to 200–300 kΩ by gold plating. Two or three tetrodes were advanced into the primary visual cortex using a manual microdrive (David Kopf Instruments). Similar penetrations were made in all experiments close to normal, to the cortical surface by tilting the micro drive back at an angle of approximately 30°. For a given penetration, we recorded activity at multiple depths typically spaced around 200 μm apart. The signal was amplified by a RA16PA Medusa preamplifier and then filtered and digitized by a RZ5 Bioamp Processor (Tucker-Davis Technologies, Alachua, FL). LFPs were filtered between 1 and 200 Hz and sampled at 509 Hz. To estimate multi-unit spiking activity (MUA), we thresholded signals that were filtered between 300 Hz and 4 kHz and sampled at 24.4 kHz, on each tetrode by using the channel with largest signal to noise ratio. We focus on MUA because a major goal of the study was to relate BF stimulation related LFP spectral changes to effects on spiking activity at various V1 sites, requiring a single spiking activity related signal for each V1 recording site, as well as for direct comparability to our previous pharmacological work . For a subset of analyses related to orientation selectivity and contrast sensitivity, we additionally examined results for single unit activity (SUA) for a population of well-isolated neurons (n=84). SUA was isolated using manual tetrode clustering software (MClust, http://umn.edu/~redish/mclust).
At the end of a recording session, we made reference lesions at multiple depths both in the visual cortex and along the penetration to the NBM using a constant current stimulator (WPI A360). Lesions were made by passing 10 μA for 10s in V1, and 250 μA for 30 or 60s in the BF. Animals were then perfused through the heart with 0.9% NaCl followed by ice cold 4% PFA in 0.1M phosphate buffer (pH 7.4). The top of the skull was removed, and stereotactic coronal cuts were made through the brain allowing the extraction of brain segments containing V1 and BF respectively. The brain was then removed and immersed in a mixture of 2% DMSO and first 10% and later 20% glycerol in 0.1M phosphate buffer (pH 7.4). The V1 brain segment was cut into 50 μm sagittal sections and the BF segment into 50 μm coronal sections using a freezing microtome (Microm HM440E). Cytochrome oxidase immunohistochemistry was performed on the sections for the localization of the lesions . In V1, recording locations were assigned to layers (supragranular, granular and infragranular) based on anatomical reconstruction of recording positions using histology when possible (n=4 animals), and estimated based on actual recording depth and average borders between layers correcting for the non-perpendicular angle of tetrode penetration (n=2 animals) .
Electrical and visual stimuli
Electrical stimulation pulse trains were generated with a Pulsar 6i (FHC, Bowdoinham, ME 04008, USA) and usually consisted of a 500 ms long train of constant 7 to 10V positive pulses of 50 μs duration at 100Hz delivered through one of the two wires of the stereotrode only (unipolar stimulation; the return path being the ground screw). Visual stimuli were generated with Psychophysics Toolbox running on a Mac Mini and presented on a gamma corrected 21” diameter (56.7° visual angle) Compaq Qvision 210 cathode ray tube monitor running at 119.22 Hz. Maximum luminance measured with a Minolta TV-color analyzer was determined as 50 cd/m2. Before recording neural activity, we mapped the approximate location of the receptive fields of the neurons under study by manually sliding bars generated with a simple graphics program back and forth on the monitor.
For this study we used two different stimulation paradigms: In the “BF stim only” protocol we presented a blank screen of intermediate luminance for the entire length of the recording, collecting at least 30 seconds of spontaneous activity and then electrically stimulated the BF five times with 30s inter stimulation interval. The “BF stim grating” protocol consisted of two blocks (a) visual stimulation using drifting gratings in conjunction with BF stimulation and (b) visual stimulation alone as a control. Drifting sinusoidal gratings were presented at a fixed, manually determined optimal speed (1–3 cycles per second) and spatial frequency (0.03 - 0.7 cycles per visual degree), were chosen to be large enough to cover all simultaneously recorded receptive fields and ranged from 10 to 30 degrees. We showed three different contrast conditions (between 10 and 100%) and eight drift directions spaced uniformly at 45° intervals – note that these conditions correspond to 4 different orientations, each drifting in two opposite directions. The set of 24 different stimuli was presented five times in different pseudorandom order. Each stimulus was shown for two seconds with one second inter-stimulus blank period. In the blocks with the interleaved electrical stimulation, we stimulated the BF before every visual stimulus, immediately following the one second inter-stimulus interval.
For the “BF stim only” protocol we analyzed the power spectral density (PSD) of the LFP activity using the Matlab implementation of Thomsons multitaper method (function: pmtm, nw = 3, nfft = 1024, fs = 1000, yielding a frequency resolution of ~1Hz) in five, non-overlapping, two second windows before the first BF stimulation and the first two-second window immediately after each BF stimulation, taking care not to include any part of the electrical stimulation artifact. This yielded five independent estimates of the PSD before, and five estimates immediately following each BF stimulation. For further analysis we averaged the PSD estimates between 1 and 10 Hz and between 30 and 90 Hz (11 and 62 frequency bins respectively) across the five repetitions. We report the logarithmic ratio of BF stimulation to control PSD as the PSD ratio for both low and high frequency bands. Visual inspection of the PSD spectra revealed that BF stimulation often resulted in spectral peaks in the “BF stim only” condition without visual stimulation. We observed that peaks occurred near center frequencies of 40 Hz and 70 Hz, with both peaks sometimes occurring together. We determined the borders of each apparent spectral peak by visual inspection, and used this information to compute PSD ratios for each peak occurrence as above. For the changes in visual responses after BF stimulation, we compared the firing rates of each unit in response to the drifting grating stimulus during the two second visual stimulation period with and without preceding electrical BF stimulation. Note that the sequence of BF stimulation followed by sensory processing is somewhat artificial, since during task performance BF neurons are activated after sensory processing of incoming stimuli [82, 83].
Orientation preference and contrast response function
The vectors of the responses to the full contrast gratings R(θ i ) to each orientation θ i are added up in the complex plane and then normalized by the sum of all responses. The OSI takes a value between 0 for untuned and 1 for perfectly tuned responses. OSI values were computed for 72/84 single neurons and 87/87 MUA sites that exhibited sufficient firing rates (>2 Hz) to allow reliable estimates.
Where μ is the predicted preferred orientation, A the amplitude of the Gaussian and A 0 the offset from zero. TH corresponds toA, and TW is defined as full width at half height, calculated as . We obtained good fits for 60/84 single neurons and 64/87 MUA sites.
For the contrast analyses, we averaged data at each contrast across all drifting directions, so that each data point represents a mean of 5×8 = 40 trials. We fitted Naka-Rushton functions to the contrast response curve: , where the parameters baseline-subtracted peak firing rate (Rmax), baseline firing rate (R0) and the semi-saturation contrast (C50) are obtained. The C50 is inversely related to the contrast sensitivity: the smaller the C50, the higher the contrast sensitivity. Reported p-values were calculated using a paired t-test as data were normally distributed according to a Kolmogorov-Smirnov test (p<0.05); We obtained good fits for 72/84 single neurons and 84/87 MUA sites.
Nucleus centralis amygdalae
Contrast response function
Deep brain stimulation
Local field potential
Muscarinic ACh receptor
Multi unit activity
Nicotinic ACh receptor
Nucleus basalis of Meynert
Nucleus fasciculi diagonalis Brocae
Orientation selectivity index
Power spectral density
Primary visual cortex.
We thank Christine Roulin, André Gaillard for technical assistance. This work was supported by SNF grant PDFMP3_127179/1, a EURYI award to GR and the University of Fribourg.
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