Basal Forebrain Stimulation Research Articles

Development of individualized transcranial ultrasonic stimulation of the human basal forebrain with concurrent functional neuroimaging

Development of individualized transcranial ultrasonic stimulation of the human basal forebrain with concurrent functional neuroimaging

Development and evaluation of an experimental setup for combining transcranial ultrasonic stimulation of the human basal forebrain with simultaneous electroencephalography

Development and evaluation of an experimental setup for combining transcranial ultrasonic stimulation of the human basal forebrain with simultaneous electroencephalography

Inactivation of Prefrontal Cortex Attenuates Behavioral Arousal Induced by Stimulation of Basal Forebrain During Sevoflurane Anesthesia.

BACKGROUND:Cholinergic stimulation of prefrontal cortex (PFC) can reverse anesthesia. Conversely, inactivation of PFC can delay emergence from anesthesia. PFC receives cholinergic projections from basal forebrain, which contains wake-promoting neurons. However, the role of basal forebrain cholinergic neurons in arousal from the anesthetized state requires refinement, and it is currently unknown whether the arousal-promoting effect of basal forebrain is mediated through PFC. To address these gaps in knowledge, we implemented a novel approach to the use of chemogenetic stimulation and tested the role of basal forebrain cholinergic neurons in behavioral arousal during sevoflurane anesthesia. Next, we investigated the effect of tetrodotoxin-mediated inactivation of PFC on behavioral arousal produced by electrical stimulation of basal forebrain during sevoflurane anesthesia.METHODS:Adult male and female transgenic rats (Long-Evans-Tg [ChAT-Cre]5.1 Deis; n = 22) were surgically prepared for expression of excitatory hM3D(Gq) receptors or mCherry in basal forebrain cholinergic neurons, and activation of these neurons by local delivery of compound 21, an agonist for hM3D(Gq) receptors. The transgenic rats were fitted with microdialysis probes for agonist delivery into basal forebrain and simultaneous prefrontal acetylcholine measurement. Adult male and female Sprague Dawley rats were surgically prepared for bilateral electrical stimulation of basal forebrain and tetrodotoxin infusion (156 μM and 500 nL) into PFC (n = 9) or bilateral electrical stimulation of piriform cortex (n = 9) as an anatomical control. All rats were implanted with electrodes to monitor the electroencephalogram. Heart and respiration rates were monitored using noninvasive sensors. A 6-point scale was used to score behavioral arousal (0 = no arousal and 5 = return of righting reflex).RESULTS:Compound 21 delivery into basal forebrain of rats with hM3D(Gq) receptors during sevoflurane anesthesia produced increases in arousal score (P < .001; confidence interval [CI], 1.80–4.35), heart rate (P < .001; CI, 36.19–85.32), respiration rate (P < .001; CI, 22.81–58.78), theta/delta ratio (P = .008; CI, 0.028–0.16), and prefrontal acetylcholine (P < .001; CI, 1.73–7.46). Electrical stimulation of basal forebrain also produced increases in arousal score (P < .001; CI, 1.85–4.08), heart rate (P = .018; CI, 9.38–98.04), respiration rate (P < .001; CI, 24.15–53.82), and theta/delta ratio (P = .020; CI, 0.019–0.22), which were attenuated by tetrodotoxin-mediated inactivation of PFC.CONCLUSIONS:This study validates the role of basal forebrain cholinergic neurons in behavioral arousal and demonstrates that the arousal-promoting effects of basal forebrain are mediated in part through PFC.

Arousal Promoting Effects of Basal Forebrain are Mediated through Prefrontal Cortex in Rat

Background We recently showed that cholinergic stimulation of prefrontal cortex (PFC), via local carbachol delivery, increased local acetylcholine (ACh) levels and restored wakefulness in sevoflurane-anesthetized rats.[1] PFC receives cholinergic projections from basal forebrain (BF), and activation of cholinergic BF neurons has been shown to promote behavioral arousal.[2] Increase in prefrontal ACh during carbachol-induced wake state reflects BF activation, but it is not known if BF acts via PFC to promote behavioral arousal. The objective of the current study is to test the hypothesis that PFC gates the arousal promoting effects of BF. Methods Under isoflurane anesthesia, Sprague Dawley rats (n=3) were implanted with bipolar wire electrodes (500um diameter) bilaterally into BF (Bregma: posterior 0.48mm, mediolateral 2.0mm, ventral 8.2mm), screw electrodes across the cortex to record electroencephalogram (EEG), and a bilateral guide cannula aimed at PFC (Bregma: anterior 3.0mm, mediolateral 0.5mm, ventral 4.0mm). Another group of Sprague Dawley rats (n=2) was implanted with the electrical stimulation electrodes into piriform cortex (Bregma: posterior 0.48mm, mediolateral 5.0mm, ventral 9.0mm), as a control anatomical site. All coordinates are as per the stereotaxic atlas by Paxinos and Watson.[3] After 7-10 days of post-surgical recovery, we conducted bilateral constant current electrical stimulation of BF (200Hz, 30s ON and 30s OFF - three cycles at 60uA and three cycles at 100uA) in sevoflurane-anesthetized rats (1.9-2.4%) with or without concurrent inactivation of PFC via local bilateral infusion of tetrodotoxin (156µM, 500nL). The same paradigm was used for electrical stimulation of piriform cortex. Results Electrical stimulation of BF in sevoflurane-anesthetized rats induced signs of behavioral arousal (whisker, orofacial and limb movements, and attempts at/regaining of the righting reflex), activated the EEG, and increased the heart (~13%) and respiration (~67%) rate. By contrast, electrical stimulation of BF in the presence of tetrodotoxin in PFC failed to induce behavioral arousal and EEG activation. Electrical stimulation of the control anatomical site (piriform cortex) in sevoflurane-anesthetized rat did not induce behavioral arousal. Conclusions These results suggest that the arousal promoting effects of BF are gated through PFC, potentially through a cholinergic circuit.

Distribution and mRNA Expression of nAChRs in the Rat S1 and M1 Cortices After Electrical Stimulation of the Basal Forebrain.

To study the changes in the distribution of and the transcriptional levels associated with α4- and α7-subtype nicotinic acetylcholine receptors (nAChRs) in the primary somatosensory (S1) and motor (M1) cortices of rats after electrical stimulation of the basal forebrain (BF). Immunofluorescence (IF) analyses were performed on brain sections from 20 rats (experimental groups: controls, contralateral, and ipsilateral to BF stimulation). The nAChR receptor complexes were labeled with antibodies and counted (N) in the cortical layers of the hindlimb representation (S1HL), barrel field (S1BF), and M1. To determine the relative transcriptional mRNA levels, qRT-PCR was performed with tissue from the associated brain regions of 14 different animals in two groups, controls and BF stimulation. For all three tested brain regions, N and D (density) of the α7-subtype nAChR increased in both ipsilateral and contralateral hemispheres after BF stimulation. There was no change in N and D of the α4 subtype. Regardless of BF stimulation, N of both subtypes was lower in M1 compared to S1HL and S1BF, and D was highest in layers II-IV. BF stimulation had no significant effect on the relative mRNA levels of both receptor subtypes. The results show an upregulation of the α7-subtype nAChR as a result of BF stimulation, based on receptor-complex counts on IF images. However, this change was not reflected in mRNA levels, which suggest post-translational modifications. Overall, this study suggests structural changes from the effects of cholinergic projections to the somatosensory and motor cortices.

Optogenetic Stimulation of Basal Forebrain Parvalbumin Neurons Activates the Default Mode Network and Associated Behaviors

Activation of the basal forebrain (BF) has been associated with increased attention, arousal, and a heightened cortical representation of the external world. In addition, BF has been implicated in the regulation of the default mode network (DMN) and associated behaviors. Here, we provide causal evidence for a role of BF in DMN regulation, highlighting a prominent role of parvalbumin (PV) GABAergic neurons. The optogenetic activation of BF PV neurons reliably drives animals toward DMN-like behaviors, with no effect on memory encoding. In contrast, BF electrical stimulation enhances memory performance and increases DMN-like behaviors. BF stimulation has a correlated impact on peptide regulation in the BF and ACC, enhancing peptides linked to grooming behavior and memory functions, supporting a crucial role of the BF in DMN regulation. We suggest that in addition to enhancing attentional functions, the BF harbors a network encompassing PV GABAergic neurons that promotes self-directed behaviors associated with the DMN.

Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia.

Increases in broadband cortical electroencephalogram (EEG) power in the gamma band (30–80 Hz) range have been observed in schizophrenia patients and in mouse models of schizophrenia. They are also seen in humans and animals treated with the psychotomimetic agent ketamine. However, the mechanisms which can result in increased broadband gamma power and the pathophysiological implications for cognition and behavior are poorly understood. Here we report that tonic optogenetic manipulation of an ascending arousal system bi-directionally tunes cortical broadband gamma power, allowing on-demand tests of the effect on cortical processing and behavior. Constant, low wattage optogenetic stimulation of basal forebrain (BF) neurons containing the calcium-binding protein parvalbumin (PV) increased broadband gamma frequency power, increased locomotor activity, and impaired novel object recognition. Concomitantly, task-associated gamma band oscillations induced by trains of auditory stimuli, or exposure to novel objects, were impaired, reminiscent of findings in schizophrenia patients. Conversely, tonic optogenetic inhibition of BF-PV neurons partially rescued the elevated broadband gamma power elicited by subanesthetic doses of ketamine. These results support the idea that increased cortical broadband gamma activity leads to impairments in cognition and behavior and identify BF-PV activity as a modulator of this activity. As such, BF-PV neurons may represent a novel target for pharmacotherapy in disorders such as schizophrenia which involve aberrant increases in cortical broadband gamma activity.

Effects of basal forebrain stimulation on the vibrotactile responses of neurons from the hindpaw representation in the rat SI cortex.

Basal forebrain (BF) cholinergic system is important for attention and modulates sensory processing. We focused on the hindpaw representation in rat primary somatosensory cortex (S1), which receives inputs related to mechanoreceptors identical to those in human glabrous skin. Spike data were recorded from S1 tactile neurons (n = 87) with (ON condition: 0.5-ms bipolar current pulses at 100Hz; amplitude 50μA, duration 0.5s at each trial) and without (OFF condition) electrical stimulation of BF in anesthetized rats. We expected that prior activation of BF would induce changes in the vibrotactile responses of neurons during sinusoidal (5, 40, and 250Hz) mechanical stimulation of the glabrous skin. The experiment consisted of sequential OFF-ON conditions in two-time blocks separated by 30min to test possible remaining effects. Average firing rates (AFRs) and vector strengths of spike phases (VS) were analyzed for different neuron types [regular spiking (RS) and fast spiking (FS)] in different cortical layers (III-VI). Immediate effect of BF activation was only significant by increasing synchronization to 5-Hz vibrotactile stimulus within the second block. Regardless of frequency, ON-OFF paired VS differences were significantly higher in the second block compared to the first, more prominent for RS neurons, and in general for neurons in layers III and VI. No such effects could be found on AFRs. The results suggest that cholinergic activation induces some changes in the hindpaw area, enabling relatively higher increases in synchronization to vibrotactile inputs with subsequent BF modulation. In addition, this modulation depends on neuron type and layer, which may be related to detailed projection pattern from BF.

Role of the Thalamus in Basal Forebrain Regulation of Neural Activity in the Primary Auditory Cortex.

Many studies have implicated the basal forebrain (BF) as a potent regulator of sensory encoding even at the earliest stages of or cortical processing. The source of this regulation involves the well-documented corticopetal cholinergic projections from BF to primary cortical areas. However, the BF also projects to subcortical structures, including the thalamic reticular nucleus (TRN), which has abundant reciprocal connections with sensory thalamus. Here we present naturalistic auditory stimuli to the anesthetized rat while making simultaneous single-unit recordings from the ventral medial geniculate nucleus (MGN) and primary auditory cortex (A1) during electrical stimulation of the BF. Like primary visual cortex, we find that BF stimulation increases the trial-to-trial reliability of A1 neurons, and we relate these results to change in the response properties of MGN neurons. We discuss several lines of evidence that implicate the BF to thalamus pathway in the manifestation of BF-induced changes to cortical sensory processing and support our conclusions with supplementary TRN recordings, as well as studies in awake animals showing a strong relationship between endogenous BF activity and A1 reliability. Our findings suggest that the BF subcortical projections that modulate MGN play an important role in auditory processing.

The lateral preoptic area and ventral pallidum embolden behavior

While recently completing a study of the effects of stimulating the lateral preoptic area (LPO) and ventral pallidum (VP) on locomotion and other movements, we also noticed LPO and VP effects on motivational drive and threat tolerance. Here, we have investigated these latter effects by testing conditioned place preference (CPP), behavior on the elevated plus maze (EPM) and the willingness of sated rats to occupy a harshly lit open field center to acquire sweet pellets, a measure of threat tolerance, following infusions of vehicle or bicuculline (bic) into the LPO and VP. LPO-bic infusions robustly increased total locomotion, and, in direct proportion, occupancy of both the harshly lit field center and open arms of the EPM. LPO bic also generated CPP, but did not increase sweet pellet ingestion. These effects were attenuated by dopamine D1 and D2 receptor antagonists, whether given individually or as a cocktail and systemically or infused bilaterally into the nucleus accumbens. VP-bic infusions did not increase total locomotion, but preferentially increased field center occupancy. VP-bic-infused rats compulsively ingested sweet pellets and did so even under the spotlight, whereas harsh illumination suppressed pellet ingestion in the control groups. VP bic produced CPP and increased open arm occupancy on the EPM. These effects were attenuated by pretreatment with dopamine receptor antagonists given systemically or as bilateral infusions into the VP, except for % distance in the field center (by D1 or D2 antagonists) and pellet ingestion (by D1 antagonist). Thus, boldness generated in association with LPO activation is tightly tied to locomotor activation and, as is locomotion itself, strongly DA dependent, whereas that accompanying stimulation of the VP is independent of locomotor activation and, at least in part, DA signaling. Furthermore, respective emboldened behaviors elicited from neither LPO nor VP could clearly be attributed to goal pursuit. Rather, emboldening of behavior seems more to be a fixed action response not fundamentally different than previously for reported locomotion, pivoting, backing, gnawing, and eating elicited by basal forebrain stimulation.

Basal forebrain activation enhances between-trial reliability of low-frequency local field potentials (LFP) and spiking activity in tree shrew primary visual cortex (V1).

Brain state has profound effects on neural processing and stimulus encoding in sensory cortices. While the synchronized state is dominated by low-frequency local field potential (LFP) activity, low-frequency LFP power is suppressed in the desynchronized state, where a concurrent enhancement in gamma power is observed. Recently, it has been shown that cortical desynchronization co-occurs with enhanced between-trial reliability of spiking activity in sensory neurons, but it is currently unclear whether this effect is also evident in LFP signals. Here, we address this question by recording both spike trains and LFP in primary visual cortex during natural movie stimulation, and using isoflurane anesthesia and basal forebrain (BF) electrical activation as proxies for synchronized and desynchronized brain states. We show that indeed, low-frequency LFP modulations ("LFP events") also occur more reliably following BF activation. Interestingly, while being more reliable, these LFP events are smaller in amplitude compared to those generated in the synchronized brain state. We further demonstrate that differences in reliability of spiking activity between cortical states can be linked to amplitude and probability of LFP events. The correlated temporal dynamics between low-frequency LFP and spiking response reliability in visual cortex suggests that these effects may both be the result of the same neural circuit activation triggered by BF stimulation, which facilitates switching between processing of incoming sensory information in the desynchronized and reverberation of internal signals in the synchronized state.

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior.

State-dependent and cell type-specific temporal processing in auditory thalamocortical circuit.

Ongoing spontaneous activity in cortical circuits defines cortical states, but it still remains unclear how cortical states shape sensory processing across cortical laminae and what type of response properties emerge in the cortex. Recording neural activity from the auditory cortex (AC) and medial geniculate body (MGB) simultaneously with electrical stimulations of the basal forebrain (BF) in urethane-anesthetized rats, we investigated state-dependent spontaneous and auditory-evoked activities in the auditory thalamocortical circuit. BF stimulation induced a short-lasting desynchronized state, with sparser firing and increased power at gamma frequency in superficial layers. In this desynchronized state, the reduction in onset response variability in both AC and MGB was accompanied by cell type-specific firing, with decreased responses of cortical broad spiking cells, but increased responses of cortical narrow spiking cells. This onset response was followed by distinct temporal evolution in AC, with quicker rebound firing in infragranular layers. This temporal profile was associated with improved processing of temporally structured stimuli across AC layers to varying degrees, but not in MGB. Thus, the reduction in response variability during the desynchronized state can be seen subcortically whereas the improvement of temporal tuning emerges across AC layers, emphasizing the importance of state-dependent intracortical processing in hearing.

Neurovascular coupling during cortical spreading depolarization and -depression.

Cortical spreading depolarizations (CSDs) are self-propagating waves of transient loss of neuronal transmembrane ion gradients, followed by prolonged suppression of neuronal activity (spreading depression). CSDs emerge spontaneously in animal models of traumatic brain injury,1 subarachnoid hemorrhage,2 and in focal ischemia3 where they are associated with infarct growth.4 In humans, CSDs have been demonstrated in traumatic brain injury,5 subarachnoid hemorrhage,6,7 and malignant hemispheric stroke,8 and they are believed to be the brain mechanism underlying migraine aura.9 CSDs are associated with dramatic changes in cerebral blood flow (CBF). During the depolarization phase of CSDs induced in healthy and well-perfused brain tissue in animal models, an early hyperemic response is observed, typically followed by prolonged oligemia after the neuronal repolarization. Despite the initial CBF increase, tissue hypoxia may develop in more distant territories of capillary supply.10,11 Similar CBF changes have been observed in patients with migraine aura.12–14 In the injured brain, CSDs can be accompanied by severe initial CBF reduction instead of a CBF increase during the depolarization phase, termed spreading ischemia.15 When this inverse hemodynamic response is observed, the energy-dependent recovery from CSD is delayed in a characteristic fashion, indicating a severe mismatch between oxygen supply and demand2 and a high risk of tissue damage.16 In rat and cat models of focal ischemia, CSD-related CBF transients range from monophasic, positive CBF responses in peri-ischemic tissue, over biphasic transients in mildly ischemic tissue, to negative CBF transients in more severe ischemia.17–19 During CSD in animal models, capillary flow patterns become severely disturbed.10,20,21 The passage of a CSD causes erythrocytes in some capillaries to reduce their speed, whereas other capillaries reveal 4-fold increases in flow or higher. …

Spectroscopic measurement of cortical nitric oxide release induced by ascending activation

The transition from sleep to the awake state is regulated by the activation of subcortical nuclei of the brainstem (BS) and basal forebrain (BF), releasing acetylcholine and glutamate throughout the cortex and inducing a tonic state of neural activity. It has been suggested that such activation is also mediated by the massive and diffuse cortical release of nitric oxide (NO). In this work we have combined the spectroscopic measurement of NO levels in the somatosensory cortex of the cat through its marker methemoglobin, as well as two other hemodynamic markers (oxyhemoglobin – oxyHb – and deoxyhemoglobin – deoxyHb), together with the electrical stimulation of BS and BF – to induce an experimental transition from a sleep-like state to an awake-like mode. The results show an increase of NO levels either after BS or BF activation. The response induced by BS stimulation was biphasic in the three studied markers, and lasted for up to 30s. The changes induced by BF were monophasic lasting for up to 20s. The systemic blockade of NO production abolished the observed responses to BS whereas responses to BF stimulation were much less affected. These results indicate a crucial role for NO in the neuronal activation induced by the ascending systems.

Curtailing effect of awakening on visual responses of cortical neurons by cholinergic activation of inhibitory circuits.

Visual responsiveness of cortical neurons changes depending on the brain state. Neural circuit mechanism underlying this change is unclear. By applying the method of in vivo two-photon functional calcium imaging to transgenic rats in which GABAergic neurons express fluorescent protein, we analyzed changes in visual response properties of cortical neurons when animals became awakened from anesthesia. In the awake state, the magnitude and reliability of visual responses of GABAergic neurons increased whereas the decay of responses of excitatory neurons became faster. To test whether the basal forebrain (BF) cholinergic projection is involved in these changes, we analyzed effects of electrical and optogenetic activation of BF on visual responses of mouse cortical neurons with in vivo imaging and whole-cell recordings. Electrical BF stimulation in anesthetized animals induced the same direction of changes in visual responses of both groups of neurons as awakening. Optogenetic activation increased the frequency of visually evoked action potentials in GABAergic neurons but induced the delayed hyperpolarization that ceased the late generation of action potentials in excitatory neurons. Pharmacological analysis in slice preparations revealed that photoactivation-induced depolarization of layer 1 GABAergic neurons was blocked by a nicotinic receptor antagonist, whereas non-fast-spiking layer 2/3 GABAergic neurons was blocked only by the application of both nicotinic and muscarinic receptor antagonists. These results suggest that the effect of awakening is mediated mainly through nicotinic activation of layer 1 GABAergic neurons and mixed nicotinic/muscarinic activation of layer 2/3 non-fast-spiking GABAergic neurons, which together curtails the visual responses of excitatory neurons.

Cholinergic circuit modulation through differential recruitment of neocortical interneuron types during behaviour.

Acetylcholine is a crucial neuromodulator for attention, learning and memory. Release of acetylcholine in primary sensory cortex enhances processing of sensory stimuli, and many in vitro studies have pinpointed cellular mechanisms that could mediate this effect. In contrast, how cholinergic modulation shapes the function of intact circuits during behaviour is only beginning to emerge. Here we review recent data on the recruitment of identified interneuron types in neocortex by cholinergic signalling, obtained with a combination of genetic targeting of cell types, two-photon imaging and optogenetics. These results suggest that acetylcholine release during basal forebrain stimulation, and during physiological recruitment of the basal forebrain, can strongly and rapidly influence the firing of neocortical interneurons. In contrast to the traditional view of neuromodulation as a relatively slow process, cholinergic signalling can thus rapidly convey time-locked information to neocortex about the behavioural state of the animal and the occurrence of salient sensory stimuli. Importantly, these effects strongly depend on interneuron type, and different interneuron types in turn control distinct aspects of circuit function. One prominent effect of phasic acetylcholine release is disinhibition of pyramidal neurons, which can facilitate sensory processing and associative learning.

Mechanisms underlying the basal forebrain enhancement of top-down and bottom-up attention

Both attentional signals from frontal cortex and neuromodulatory signals from basal forebrain (BF) have been shown to influence information processing in the primary visual cortex (V1). These two systems exert complementary effects on their targets, including increasing firing rates and decreasing interneuronal correlations. Interestingly, experimental research suggests that the cholinergic system is important for increasing V1's sensitivity to both sensory and attentional information. To see how the BF and top-down attention act together to modulate sensory input, we developed a spiking neural network model of V1 and thalamus that incorporated cholinergic neuromodulation and top-down attention. In our model, activation of the BF had a broad effect that decreases the efficacy of top-down projections and increased the reliance of bottom-up sensory input. In contrast, we demonstrated how local release of acetylcholine in the visual cortex, which was triggered through top-down gluatmatergic projections, could enhance top-down attention with high spatial specificity. Our model matched experimental data showing that the BF and top-down attention decrease interneuronal correlations and increase between-trial reliability. We found that decreases in correlations were primarily between excitatory-inhibitory pairs rather than excitatory-excitatory pairs and suggest that excitatory-inhibitory decorrelation is necessary for maintaining low levels of excitatory-excitatory correlations. Increased inhibitory drive via release of acetylcholine in V1 may then act as a buffer, absorbing increases in excitatory-excitatory correlations that occur with attention and BF stimulation. These findings will lead to a better understanding of the mechanisms underyling the BF's interactions with attention signals and influences on correlations.

Visual training paired with electrical stimulation of the basal forebrain improves orientation-selective visual acuity in the rat

The cholinergic afferents from the basal forebrain to the primary visual cortex play a key role in visual attention and cortical plasticity. These afferent fibers modulate acute and long-term responses of visual neurons to specific stimuli. The present study evaluates whether this cholinergic modulation of visual neurons results in cortical activity and visual perception changes. Awake adult rats were exposed repeatedly for 2 weeks to an orientation-specific grating with or without coupling this visual stimulation to an electrical stimulation of the basal forebrain. The visual acuity, as measured using a visual water maze before and after the exposure to the orientation-specific grating, was increased in the group of trained rats with simultaneous basal forebrain/visual stimulation. The increase in visual acuity was not observed when visual training or basal forebrain stimulation was performed separately or when cholinergic fibers were selectively lesioned prior to the visual stimulation. The visual evoked potentials show a long-lasting increase in cortical reactivity of the primary visual cortex after coupled visual/cholinergic stimulation, as well as c-Fos immunoreactivity of both pyramidal and GABAergic interneuron. These findings demonstrate that when coupled with visual training, the cholinergic system improves visual performance for the trained orientation probably through enhancement of attentional processes and cortical plasticity in V1 related to the ratio of excitatory/inhibitory inputs. This study opens the possibility of establishing efficient rehabilitation strategies for facilitating visual capacity.