Cholinergic Neuromodulation of Prefrontal Attractor Dynamics Controls Performance in Spatial Working Memory.

The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the nucleus basalis (NB) of Meynert have been recently examined in two male monkeys (Qi et al., 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in the PFC.

Spatial frequency tuning of motor responses reveals differential contribution of dorsal and ventral systems to action comprehension.

Understanding object-directed actions performed by others is central to everyday life. This ability is thought to rely on the interaction between the dorsal action observation network (AON) and a ventral object recognition pathway. On this view, the AON would encode action kinematics, and the ventral pathway, the most likely intention afforded by the objects. However, experimental evidence supporting this model is still scarce. Here, we aimed to disentangle the contribution of dorsal vs. ventral pathways to action comprehension by exploiting their differential tuning to low-spatial frequencies (LSFs) and high-spatial frequencies (HSFs). We filtered naturalistic action images to contain only LSF or HSF and measured behavioral performance and corticospinal excitability (CSE) using transcranial magnetic stimulation (TMS). Actions were embedded in congruent or incongruent scenarios as defined by the compatibility between grips and intentions afforded by the contextual objects. Behaviorally, participants were better at discriminating congruent actions in intact than LSF images. This effect was reversed for incongruent actions, with better performance for LSF than intact and HSF. These modulations were mirrored at the neurophysiological level, with greater CSE facilitation for congruent than incongruent actions for HSF and the opposite pattern for LSF images. Finally, only for LSF did we observe CSE modulations according to grip kinematics. While results point to differential dorsal (LSF) and ventral (HSF) contributions to action comprehension for grip and context encoding, respectively, the negative congruency effect for LSF images suggests that object processing may influence action perception not only through ventral-to-dorsal connections, but also through a dorsal-to-dorsal route involved in predictive processing.

Excitatory-Inhibitory Synaptic Coupling in Avian Nucleus Magnocellularis.

The activity of neurons is determined by the balance between their excitatory and inhibitory synaptic inputs. Neurons in the avian nucleus magnocellularis (NM) integrate monosynaptic excitatory and polysynaptic inhibitory inputs from the auditory nerve, and transmit phase-locked output to higher auditory centers. The excitatory input is graded tonotopically, such that neurons tuned to higher frequency receive fewer, but larger, axon terminals. However, it remains unknown how the balance between excitatory and inhibitory inputs is determined in NM. We here examined synaptic and spike responses of NM neurons during stimulation of the auditory nerve in thick brain slices of chicken of both sexes, and found that the excitatory-inhibitory balance varied according to tonotopic region, ensuring reliable spike output across frequencies. Auditory nerve stimulation elicited IPSCs in NM neurons regardless of tonotopic region, but the dependence of IPSCs on intensity varied in a systematic way. In neurons tuned to low frequency, IPSCs appeared and increased in parallel with EPSCs with elevation of intensity, which expanded dynamic range by preventing saturation of spike generation. On the other hand, in neurons tuned to higher frequency, IPSCs were smaller than EPSCs and had higher thresholds for activation, thus facilitating high-fidelity transmission. Computer simulation confirmed that these differences in inhibitory input were optimally matched to the patterns of excitatory input, and enabled appropriate level of neuronal output for wide intensity and frequency ranges of sound in the auditory system.SIGNIFICANCE STATEMENT Neurons in nucleus magnocellularis encode timing information of sound across wide intensity ranges by integrating excitatory and inhibitory synaptic inputs from the auditory nerve, but underlying synaptic mechanisms of this integration are not fully understood. We here show that the excitatory-inhibitory relationship was expressed differentially at each tonotopic region; the relationship was linear in neurons tuned to low-frequency, expanding dynamic range by preventing saturation of spike generation; by contrast inhibitory input remained much smaller than excitatory input in neurons tuned to higher frequency, thus ensuring high-fidelity transmission. The tonotopic regulation of excitatory and inhibitory input optimized the output across frequencies and intensities, playing a fundamental role in the timing coding pathway in the auditory system.

Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory.

Retrieval deficit of long-term memory is a cardinal symptom of dementia and has been proposed to associate with abnormalities in the central cholinergic system. Difficulty in the retrieval of memory is experienced by healthy individuals and not limited to patients with neurological disorders that result in forgetfulness. The difficulty of retrieving memories is associated with various factors, such as how often the event was experienced or remembered, but it is unclear how the cholinergic system plays a role in the retrieval of memory formed by a daily routine (accumulated experience). To investigate this point, we trained rats moderately (for a week) or extensively (for a month) to detect a visual cue in a two-alternative forced-choice task. First, we confirmed the well-established memory in the extensively trained group was more resistant to the retrieval problem than recently acquired memory in the moderately trained group. Next, we tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. Pre-administration of donepezil improved performance and reduced the latency of task initiation compared to the saline-treated group. Finally, we lesioned cholinergic neurons of the nucleus basalis magnocellularis (NBM), which project to the entire neocortex, by injecting the cholinergic toxin 192 IgG-saporin. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. These results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine.

Functional Subdivisions of Magnocellular Cell Groups in Human Basal Forebrain: Test-Retest Resting-State Study at Ultra-high Field, and Meta-analysis.

The heterogeneous neuronal subgroups of the basal forebrain corticopetal system (BFcs) have been shown to modulate cortical functions through their cholinergic, gamma-aminobutyric acid-ergic, and glutamatergic projections to the entire cortex. Although previous studies suggested that the basalo-cortical projection system influences various cognitive functions, particularly via its cholinergic component, these studies only focused on certain parts of the BFcs or nearby structures, leaving aside a more systematic picture of the functional connectivity of BFcs subcompartments. Moreover, these studies lacked the high-spatial resolution and the probability maps needed to identify specific subcompartments. Recent advances in the ultra-high field 7T functional magnetic resonance imaging (fMRI) provided potentially unprecedented spatial resolution of functional MRI images to study the subdivision of the BFcs. In this study, the BF space containing corticopetal cells was divided into 3 functionally distinct subdivisions based on functional connection to cortical regions derived from fMRI. The overall functional connection of each BFcs subdivision was examined with a test-retest study. Finally, a meta-analysis was used to study the related functional topics of each BF subdivision. Our results demonstrate distinct functional connectivity patterns of these subdivisions along the rostrocaudal axis of the BF. All three compartments have shown consistent segregation and overlap at specific target regions including the hippocampus, insula, thalamus, and the cingulate gyrus, suggesting functional integration and separation in BFcs.

Multimodal Encoding of Novelty, Reward, and Learning in the Primate Nucleus Basalis of Meynert.

Associative learning is crucial for daily function, involving a complex network of brain regions. One region, the nucleus basalis of Meynert (NBM), is a highly interconnected, largely cholinergic structure implicated in multiple aspects of learning. We show that single neurons in the NBM of nonhuman primates (NHPs; n = 2 males; Macaca mulatta) encode learning a new association through spike rate modulation. However, the power of low-frequency local field potential (LFP) oscillations decreases in response to novel, not-yet-learned stimuli but then increase as learning progresses. Both NBM and the dorsolateral prefrontal cortex encode confidence in novel associations by increasing low- and high-frequency LFP power in anticipation of expected rewards. Finally, NBM high-frequency power dynamics are anticorrelated with spike rate modulations. Therefore, novelty, learning, and reward anticipation are separately encoded through differentiable NBM signals. By signaling both the need to learn and confidence in newly acquired associations, NBM may play a key role in coordinating cortical activity throughout the learning process.SIGNIFICANCE STATEMENT Degradation of cells in a key brain region, the nucleus basalis of Meynert (NBM), correlates with Alzheimer's disease and Parkinson's disease progression. To better understand the role of this brain structure in learning and memory, we examined neural activity in the NBM in behaving nonhuman primates while they performed a learning and memory task. We found that single neurons in NBM encoded both salience and an early learning, or cognitive state, whereas populations of neurons in the NBM and prefrontal cortex encode learned state and reward anticipation. The NBM may thus encode multiple stages of learning. These multimodal signals might be leveraged in future studies to develop neural stimulation to facilitate different stages of learning and memory.

Cholinergic Modulation of Frontoparietal Cortical Network Dynamics Supporting Supramodal Attention.

A critical function of attention is to support a state of readiness to enhance stimulus detection, independent of stimulus modality. The nucleus basalis magnocellularis (NBM) is the major source of the neurochemical acetylcholine (ACh) for frontoparietal cortical networks thought to support attention. We examined a potential supramodal role of ACh in a frontoparietal cortical attentional network supporting target detection. We recorded local field potentials (LFPs) in the prelimbic frontal cortex (PFC) and the posterior parietal cortex (PPC) to assess whether ACh contributed to a state of readiness to alert rats to an impending presentation of visual or olfactory targets in one of five locations. Twenty male Long-Evans rats underwent training and then lesions of the NBM using the selective cholinergic immunotoxin 192 IgG-saporin (0.3 µg/µl; ACh-NBM-lesion) to reduce cholinergic afferentation of the cortical mantle. Postsurgery, ACh-NBM-lesioned rats had less correct responses and more omissions than sham-lesioned rats, which changed parametrically as we increased the attentional demands of the task with decreased target duration. This parametric deficit was found equally for both sensory targets. Accurate detection of visual and olfactory targets was associated specifically with increased LFP coherence, in the beta range, between the PFC and PPC, and with increased beta power in the PPC before the target's appearance in sham-lesioned rats. Readiness-associated changes in brain activity and visual and olfactory target detection were attenuated in the ACh-NBM-lesioned group. Accordingly, ACh may support supramodal attention via modulating activity in a frontoparietal cortical network, orchestrating a state of readiness to enhance target detection.SIGNIFICANCE STATEMENT We examined whether the neurochemical acetylcholine (ACh) contributes to a state of readiness for target detection, by engaging frontoparietal cortical attentional networks independent of modality. We show that ACh supported alerting attention to an impending presentation of either visual or olfactory targets. Using local field potentials, enhanced stimulus detection was associated with an anticipatory increase in power in the beta oscillation range before the target's appearance within the posterior parietal cortex (PPC) as well as increased synchrony, also in beta, between the prefrontal cortex and PPC. These readiness-associated changes in brain activity and behavior were attenuated in rats with reduced cortical ACh. Thus, ACh may act, in a supramodal manner, to prepare frontoparietal cortical attentional networks for target detection.

Membrane Potential Correlates of Network Decorrelation and Improved SNR by Cholinergic Activation in the Somatosensory Cortex.

The nucleus basalis (NB) projects cholinergic axons to the cortex, where they play a major role in arousal, attention, and learning. Cholinergic inputs shift cortical dynamics from synchronous to asynchronous and improve the signal-to-noise ratio (SNR) of sensory responses. However, the underlying mechanisms of these changes remain unclear. Using simultaneous extracellular and whole-cell patch recordings in layer 4 of the mouse barrel cortex, we show that electrical or optogenetic activation of the cholinergic system has a differential effect on ongoing and sensory evoked activities. Cholinergic activation profoundly reduced the large spontaneous fluctuations in membrane potential and decorrelated ongoing activity. However, NB stimulation had no effect on the response to whisker stimulation or on signal correlations. These effects of cholinergic activation provide a unified explanation for the increased SNR of sensory response and for the reduction in noise correlations and explain the shift into the desynchronized cortical state, which are the hallmarks of arousal and attention.SIGNIFICANCE STATEMENT Attention increases the signal-to-noise ratio (SNR) of cortical sensory response, which may reflect either reduction in background firing rate or increased sensory response. Extracellular recordings showed that attention also reduces the correlation in network activity. These effects are partially mediated by cholinergic axons from the nucleus basalis projecting to the entire cortex. To reveal the cellular and synaptic correlates of these cholinergic effects, we performed simultaneous intracellular and LFP recordings in the somatosensory cortex. Global or local cholinergic activation increased the SNR of sensory response mainly by reducing the rate and amplitude of background synaptic activity and also reduced network correlations. Therefore, coding of sensory information is enhanced by the cholinergic system mainly due to a reduction in spontaneous activity.

From eyes-closed to eyes-open: Role of cholinergic projections in EC-to-EO alpha reactivity revealed by combining EEG and MRI.

Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes-closed (EC) resting and attenuates during eyes-open (EO) resting. Research shows that the degree of EC-to-EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC-to-EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG-fMRI was recorded from twenty-one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM-visual cortex functional connectivity increase from EC to EO, the larger the EC-to-EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC-to-EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system.

Resurgent sodium current promotes action potential firing in the avian auditory brainstem.

KEY POINTS: Auditory brainstem neurons of all vertebrates fire phase-locked action potentials (APs) at high rates with remarkable fidelity, a process controlled by specialized anatomical and biophysical properties. This is especially true in the avian nucleus magnocellularis (NM) - the analogue of the mammalian anteroventral cochlear nucleus. In addition to high voltage-activated potassium (KHVA ) channels, we report, using whole cell physiology and modelling, that resurgent sodium current (INaR ) of sodium channels (NaV ) is equally important and operates synergistically with KHVA channels to enable rapid AP firing in NM. Anatomically, we detected strong NaV 1.6 expression near hearing maturation, which was less distinct during hearing development despite functional evidence of INaR , suggesting that multiple NaV channel subtypes may contribute to INaR . We conclude that INaR plays an important role in regulating rapid AP firing for NM neurons, a property that may be evolutionarily conserved for functions related to similar avian and mammalian hearing. ABSTRACT: Auditory brainstem neurons are functionally primed to fire action potentials (APs) at markedly high rates in order to rapidly encode the acoustic information of sound. This specialization is critical for survival and the comprehension of behaviourally relevant communication functions, including sound localization and distinguishing speech from noise. Here, we investigated underlying ion channel mechanisms essential for high-rate AP firing in neurons of the chicken nucleus magnocellularis (NM) - the avian analogue of bushy cells of the mammalian anteroventral cochlear nucleus. In addition to the established function of high voltage-activated potassium channels, we found that resurgent sodium current (INaR ) plays a role in regulating rapid firing activity of late-developing (embryonic (E) days 19-21) NM neurons. INaR of late-developing NM neurons showed similar properties to mammalian neurons in that its unique mechanism of an 'open channel block state' facilitated the recovery and increased the availability of sodium (NaV ) channels after depolarization. Using a computational model of NM neurons, we demonstrated that removal of INaR reduced high-rate AP firing. We found weak INaR during a prehearing period (E11-12), which transformed to resemble late-developing INaR properties around hearing onset (E14-16). Anatomically, we detected strong NaV 1.6 expression near maturation, which became increasingly less distinct at hearing onset and prehearing periods, suggesting that multiple NaV channel subtypes may contribute to INaR during development. We conclude that INaR plays an important role in regulating rapid AP firing for NM neurons, a property that may be evolutionarily conserved for functions related to similar avian and mammalian hearing.

The effects of red surrounds on visual magnocellular and parvocellular cortical processing and perception.

More than 50 years ago, Hubel and Wiesel identified a subpopulation of geniculate magnocellular (M) neurons that are suppressed by diffuse red light. Since then, many human psychophysical studies have used red and green backgrounds to study the effects of M suppression on visual task performance, as a means to better understand neurodevelopmental disorders such as dyslexia and schizophrenia. Few of these studies have explicitly assessed the relative effects of red backgrounds on the M and P (parvocellular) pathways. Here we compared the effects of red and green diffuse background illumination on well-accepted cortical M and P signatures, both physiologically through nonlinear analysis of visual evoked potentials (VEPs; N = 15), and psychophysically through pulsed and steady pedestal perceptual thresholds (N = 9 with gray pedestals and N = 8 with colored pedestals). Red surrounds reduced P-generated temporal nonlinearity in the VEPs, but they did not influence M-generated VEP signatures. The steady and pulsed pedestal results suggest that red surrounds can have different effects on M and P contrast sensitivities, depending on whether the target is colored gray or red, presented centrally or peripherally, or whether it is brighter or dimmer than the surround. Our results highlight difficulties in interpreting the effects of red backgrounds on human VEPs or perception in terms of M specific suppression.

Neuroanatomical Characteristics Associated With Response to Deep Brain Stimulation of the Nucleus Basalis of Meynert for Alzheimer's Disease.

OBJECTIVES: First reports on the application of deep brain stimulation (DBS) of the Nucleus basalis of Meynert (NBM) showed feasibility and safety of the intervention in patients with Alzheimer´s disease. However, clinical effects vary and the mechanisms of actions are still not well understood. The aim of this study was to characterize neuroimaging changes that are associated with the responsiveness to the treatment. MATERIALS AND METHODS: We examined preoperative T1-weighted MR images of ten patients with Alzheimer's disease (AD) treated with DBS of the NBM and correlated the clinical outcome with volumetric differences of cortical thickness. Subsequently, we sought to identify brain regions that carry out the clinical effects by correlating the outcome with streamlines connected to the volume of activated tissue. Clinical assessments at baseline, 6 and 12 months after the intervention included the AD Assessment Scale as well as the mini mental status examination. RESULTS: A fronto-parieto-temporal pattern of cortical thickness was found to be associated with beneficial outcome. Modulation of streamlines connected to left parietal and opercular cortices was associated with better response to the intervention. CONCLUSION: Our results indicate that patients with less advanced atrophy may profit from DBS of the NBM. We conclude that beneficial effects of the intervention are related to preserved fronto-parieto-temporal interplay.

Brain-Wide Maps of Synaptic Input to Cortical Interneurons.

Cortical inhibition is mediated by diverse inhibitory neuron types that can each play distinct roles in information processing by virtue of differences in their input sources, intrinsic properties, and innervation targets. Previous studies in brain slices have demonstrated considerable cell-type specificity in laminar sources of local inputs. In contrast, little is known about possible differences in distant inputs to different cortical interneuron types. We used the monosynaptic rabies virus system, in conjunction with mice expressing Cre recombinase in either parvalbumin-positive, somatostatin-positive (SST+), or vasoactive intestinal peptide-positive (VIP+) neurons, to map the brain-wide input to the three major nonoverlapping classes of interneurons in mouse somatosensory cortex. We discovered that all three classes of interneurons received considerable input from known cortical and thalamic input sources, as well as from probable cholinergic cells in the basal nucleus of Meynert. Despite their common input sources, these classes differed in the proportion of long-distance cortical inputs originating from deep versus superficial layers. Similar to their laminar differences in local input, VIP+ neurons received inputs predominantly from deep layers while SST+ neurons received mostly superficial inputs. These classes also differed in the amount of input they received. Cortical and thalamic inputs were greatest onto VIP+ interneurons and smallest onto SST+ neurons. SIGNIFICANCE STATEMENT: These results indicate that all three major interneuron classes in the barrel cortex integrate both feedforward and feedback information from throughout the brain to modulate the activity of the local cortical circuit. However, differences in laminar sources and magnitude of distant cortical input suggest differential contributions from cortical areas. More input to vasoactive intestinal peptide-positive (VIP+) neurons than to somatostatin-positive (SST+) neurons suggests that disinhibition of the cortex via VIP+ cells, which inhibit SST+ cells, might be a general feature of long-distance corticocortical and thalamocortical circuits.

Opposing Roles of Cholinergic and GABAergic Activity in the Insular Cortex and Nucleus Basalis Magnocellularis during Novel Recognition and Familiar Taste Memory Retrieval.

Acetylcholine (ACh) is thought to facilitate cortical plasticity during memory formation and its release is regulated by the nucleus basalis magnocellularis (NBM). Questions remain regarding which neuronal circuits and neurotransmitters trigger activation or suppression of cortical cholinergic activity. During novel, but not familiar, taste consumption, there is a significant increase in ACh release in the insular cortex (IC), a highly relevant structure for taste learning. Here, we evaluate how GABA inhibition modulates cholinergic transmission and its involvement during taste novelty processing and familiar taste memory retrieval. Using saccharin as a taste stimulus in a taste preference paradigm, we examined the effects of injecting the GABAA receptor agonist muscimol or the GABAA receptor antagonist bicuculline into the IC or NBM during learning or retrieval of an appetitive taste memory on taste preference in male Sprague Dawley rats. GABAA receptor agonism and antagonism had opposite effects on cortical ACh levels in novel taste presentation versus familiar taste recognition and ACh levels were associated with the propensity to acquire or retrieve a taste memory. These results indicate that the pattern of cortical cholinergic and GABAergic neuroactivity during novel taste exposure is the opposite of that which occurs during familiar taste recognition and these differing neurotransmitter system states may enable different behavioral consequences. Divergences in ACh and GABA levels may produce differential alterations in excitatory and inhibitory neural processes within the cortex during acquisition and retrieval. SIGNIFICANCE STATEMENT: During learning and recall, several brain structures act together. This work demonstrates interactions between cortical cholinergic and GABAergic systems during taste learning and memory retrieval. We found that the neuroactivity pattern during novel taste exposure is opposite that which occurs during familiar taste recognition. GABAA receptors must be inactive during novel tasting to enable new memory formation, but must be active and inhibiting acetylcholine release in the cortex to allow memory retrieval. These findings indicate that GABA inhibition modulates cholinergic transmission and that cholinergic-GABAergic system interactions are important during the transition from novel to familiar memory.

Resting-State Functional Connectivity of the Basal Nucleus of Meynert in Cigarette Smokers: Dependence Level and Gender Differences.

INTRODUCTION: Numerous studies have characterized impaired cerebral functioning in nicotine-addicted individuals. Whereas nicotine interacts with multiple neurotransmitters in cortical and subcortical circuits, it directly targets the cholinergic system, sourced primarily from the basal nucleus of Meynert (BNM). However, no studies have examined how this cholinergic system is influenced by cigarette smoking. Here, we addressed this gap of research. METHODS: Using a dataset from the Functional Connectome Projects, we investigated this issue by contrasting seed-based BNM connectivity of 40 current smokers and 170 age- and gender-matched nonsmokers. We followed our data analytic routines in recent work and examined differences between smokers and nonsmokers in men and women combined as well as separately. RESULTS: Compared to nonsmokers, female but not male smokers demonstrated greater positive BNM connectivity to the supplementary motor area, bilateral anterior insula, and right superior temporal/supramarginal gyri as well as greater negative connectivity to the posterior cingulate cortex and precuneus. Further, BNM connectivity to the supplementary motor area is negatively correlated to the Fagerström Test for Nicotine Dependence score in male but not female smokers. CONCLUSIONS: Along with a previous report of upregulated nicotinic acetylcholine receptor in male but not female smokers, these new findings highlight functional changes of the cholinergic systems in cigarette smokers. The results suggest sex-specific differences in cholinergic dysregulation and a need for multiple imaging modalities to capture the neural markers of nicotine addiction. IMPLICATIONS: Nicotine influences cognition via cholinergic projections of the basal forebrain to the cerebral cortex. This study examined changes in resting-state whole-brain functional connectivity of the BNM in cigarette smokers. The new findings elucidate for the first time sex differences in BNM-cerebral connectivity in cigarette smoking.

The role of basal forebrain cholinergic neurons in fear and extinction memory.

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed.

Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia.

Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and [(18)F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.

The rationale for deep brain stimulation in Alzheimer's disease.

Alzheimer's disease is a major worldwide health problem with no effective therapy. Deep brain stimulation (DBS) has emerged as a useful therapy for certain movement disorders and is increasingly being investigated for treatment of other neural circuit disorders. Here we review the rationale for investigating DBS as a therapy for Alzheimer's disease. Phase I clinical trials of DBS targeting memory circuits in Alzheimer's disease patients have shown promising results in clinical assessments of cognitive function, neurophysiological tests of cortical glucose metabolism, and neuroanatomical volumetric measurements showing reduced rates of atrophy. These findings have been supported by animal studies, where electrical stimulation of multiple nodes within the memory circuit have shown neuroplasticity through stimulation-enhanced hippocampal neurogenesis and improved performance in memory tasks. The precise mechanisms by which DBS may enhance memory and cognitive functions in Alzheimer's disease patients and the degree of its clinical efficacy continue to be examined in ongoing clinical trials.

EFFECTS OF SELECTIVE CHOLINERGIC AND GABAERGIC LESIONS OF THE NUCLEUS BASALIS MAGNOCELLULARIS ON PLACE OR RESPONCE LEARNING IN PLUS-SHAPED MAZE.

In the present study we evaluated effects of selective cholinergic or GABAergic lesions of the nucleus basalis magnocellularis (NBM) using immunotxins 192 IgG-saporin and GAT1-SAP on place and response learning in plus-shaped maze. In current behavioral paradigm rats learned food-rewarded mazes that were efficiently learned using either place or turning strategies. A histological evaluation indicated that 192 IgG-saporin lesions specifically depleted cholinergic neurons but did not result in noticeable damage to the GABAergic cells within NBM. GAT1-SAP lesions resulted extensive damage of GABAergic and a mild reduction of cholinergic NBM neurons. The results of present behavioral experiments showed, that selective lesions of cholinergic or GABAergic neurons in the NBM impair, but do not abolish, the animal's ability to learn location of rewarded arm of maze (place learning) or a skilled motor behavior (response learning). Our findings suggest the role of NBM cholinergic and GABAergic cortical projection neurons in processing of cognitive information. We suggested that lesions of NBM projections to the cortex modulate learning-mediated plasticity and impair both place and response learning.

Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes.

Although cholinergic innervation of the cortex by the nucleus basalis (NB) is known to modulate cortical neuronal responses and instruct cortical plasticity, little is known about the underlying cellular mechanisms. Using cell-attached recordings in vivo, we demonstrate that electrical stimulation of the NB, paired with visual stimulation, can induce significant potentiation of visual responses in excitatory neurons of the primary visual cortex in mice. We further show with in vivo two-photon calcium imaging, ex vivo calcium imaging, and whole-cell recordings that this pairing-induced potentiation is mediated by direct cholinergic activation of primary visual cortex astrocytes via muscarinic AChRs. The potentiation is absent in conditional inositol 1,4,5 trisphosphate receptor type 2 KO mice, which lack astrocyte calcium activation, and is stimulus-specific, because pairing NB stimulation with a specific visual orientation reveals a highly selective potentiation of responses to the paired orientation compared with unpaired orientations. Collectively, these findings reveal a unique and surprising role for astrocytes in NB-induced stimulus-specific plasticity in the cerebral cortex.