Cholinergic Reinforcement Signaling Is Impaired by Amyloidosis Prior to Its Synaptic Loss.

Alzheimer's disease (AD) is associated with amyloidosis and dysfunction of the cholinergic system, which is crucial for learning and memory. However, the nature of acetylcholine signaling within regions of cholinergic-dependent plasticity and how it changes with experience is poorly understood, much less the impact of amyloidosis on this signaling. Therefore, we optically measure the release profile of acetylcholine to unexpected, predicted, and predictive events in visual cortex (VC)-a site of known cholinergic-dependent plasticity-in a preclinical mouse model of AD that develops amyloidosis. We find that acetylcholine exhibits reinforcement signaling qualities, reporting behaviorally relevant outcomes and displaying release profiles to predictive and predicted events that change as a consequence of experience. We identify three stages of amyloidosis occurring before the degeneration of cholinergic synapses within VC and observe that cholinergic responses in amyloid-bearing mice become impaired over these stages, diverging progressively from age- and sex-matched littermate controls. In particular, amyloidosis degrades the signaling of unexpected rewards and punishments, and attenuates the experience-dependent (1) increase of cholinergic responses to outcome predictive visual cues, and (2) decrease of cholinergic responses to predicted outcomes. Hyperactive spontaneous acetylcholine release occurring transiently at the onset of impaired cholinergic signaling is also observed, further implicating disrupted cholinergic activity as an early functional biomarker in AD. Our findings suggest that acetylcholine acts as a reinforcement signal that is impaired by amyloidosis before pathologic degeneration of the cholinergic system, providing a deeper understanding of the effects of amyloidosis on acetylcholine signaling and informing future interventions for AD.SIGNIFICANCE STATEMENT The cholinergic system is especially vulnerable to the neurotoxic effects of amyloidosis, a hallmark of Alzheimer's disease (AD). Though amyloid-induced cholinergic synaptic loss is thought in part to account for learning and memory impairments in AD, little is known regarding how amyloid impacts signaling of the cholinergic system before its anatomic degeneration. Optical measurement of acetylcholine (ACh) release in a mouse model of AD that develops amyloidosis reveals that ACh signals reinforcement and outcome prediction that is disrupted by amyloidosis before cholinergic degeneration. These observations have important scientific and clinical implications: they implicate ACh signaling as an early functional biomarker, provide a deeper understanding of the action of acetylcholine, and inform on when and how intervention may best ameliorate cognitive decline in AD.

Spectral analysis and kinetic modeling of radioluminescence in air and nitrogen.

In this article we present a quantitative analysis of the second positive system of molecular nitrogen and the first negative system of the molecular nitrogen cation excited in the presence of ionizing radiation. Optical emission spectra of atmospheric air and nitrogen surrounding 210Po sources were measured from 250 to 400 nm. Multi-Boltzmann and non-Boltzmann vibrational distribution spectral models were used to determine the vibrational temperature and vibrational distribution function of the emitting N2(C3Πu) and N2+(B2Σ+u) states. A zero-dimensional kinetic model, based on the electron energy distribution function (EEDF) and steady-state excitation and de-excitation of N2(X1Σ+g), N2+(B2Σ+u), N2+(X2Σ+g), N4+, O2+, and N2(C3Πu, v), was developed for the prediction of the relative spectral intensity of both the N2+(B2Σ+u → X2Σ+g) emission band and the vibrational bands of N2(C3Πu → B3Πg) for comparison with the experimental data.

Desymmetrization of Diols by Phosphorylation with a Titanium-BINOLate Catalyst.

The desymmetrization of ten prochiral diols by phosphoryl transfer with a titanium-BINOLate complex is discussed. The phosphorylation of nine 1,3-propane diols is achieved in yields of 50-98%. Enantiomeric ratios as high as 92:8 are achieved with diols containing a quaternary C-2 center incorporating a protected amine. The chiral ligand, base, solvent, and stoichiometry are evaluated along with a nonlinear effect study to support an active catalyst species that is oligomeric in chiral ligand. The use of pyrophosphates as the phosphorylating agent in the desymmetrization facilitates a user-friendly method for enantioselective phosphorylation with desirable protecting groups (benzyl, o-nitrobenzyl) on the phosphate product.

Dietary strawberry improves cognition in a randomised, double-blind, placebo-controlled trial in older adults.

Functional changes in the brain during ageing can alter learning and memory, gait and balance - in some cases leading to early cognitive decline, disability or injurious falls among older adults. Dietary interventions with strawberry (SB) have been associated with improvements in neuronal, psychomotor and cognitive functions in rodent models of ageing. We hypothesised that dietary supplementation with SB would improve mobility and cognition among older adults. In this study, twenty-two men and fifteen women, between the ages of 60 and 75 years, were recruited into a randomised, double-blind, placebo-controlled trial in which they consumed either freeze-dried SB (24 g/d, equivalent to two cups of fresh SB) or a SB placebo for 90 d. Participants completed a battery of balance, gait and cognitive tests at baseline and again at 45 and 90 d of intervention. Significant supplement group by study visit interactions were observed on tests of learning and memory. Participants in the SB group showed significantly shorter latencies in a virtual spatial navigation task (P = 0·020, ηp2 = 0·106) and increased word recognition in the California Verbal Learning test (P = 0·014, ηp2 = 0·159) across study visits relative to controls. However, no improvement in gait or balance was observed. These findings show that the addition of SB to the diets of healthy, older adults can improve some aspects of cognition, but not gait or balance, although more studies with a larger sample size and longer follow-up are needed to confirm this finding.

Reward Timing and Its Expression by Inhibitory Interneurons in the Mouse Primary Visual Cortex.

The primary sensory cortex has historically been studied as a low-level feature detector, but has more recently been implicated in many higher-level cognitive functions. For instance, after an animal learns that a light predicts water at a fixed delay, neurons in the primary visual cortex (V1) can produce "reward timing activity" (i.e., spike modulation of various forms that relate the interval between the visual stimulus and expected reward). Local manipulations to V1 implicate it as a site of learning reward timing activity (as opposed to simply reporting timing information from another region via feedback input). However, the manner by which V1 then produces these representations is unknown. Here, we combine behavior, in vivo electrophysiology, and optogenetics to investigate the characteristics of and circuit mechanisms underlying V1 reward timing in the head-fixed mouse. We find that reward timing activity is present in mouse V1, that inhibitory interneurons participate in reward timing, and that these representations are consistent with a theorized network architecture. Together, these results deepen our understanding of V1 reward timing and the manner by which it is produced.

Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical.

All cells obtain 2'-deoxyribonucleotides for DNA synthesis through the activity of a ribonucleotide reductase (RNR). The class I RNRs found in humans and pathogenic bacteria differ in (i) use of Fe(II), Mn(II), or both for activation of the dinuclear-metallocofactor subunit, ß; (ii) reaction of the reduced dimetal center with dioxygen or superoxide for this activation; (iii) requirement (or lack thereof) for a flavoprotein activase, NrdI, to provide the superoxide from O2; and (iv) use of either a stable tyrosyl radical or a high-valent dimetal cluster to initiate each turnover by oxidizing a cysteine residue in the α subunit to a radical (Cys•). The use of manganese by bacterial class I, subclass b-d RNRs, which contrasts with the exclusive use of iron by the eukaryotic Ia enzymes, appears to be a countermeasure of certain pathogens against iron deprivation imposed by their hosts. Here, we report a metal-free type of class I RNR (subclass e) from two human pathogens. The Cys• in its α subunit is generated by a stable, tyrosine-derived dihydroxyphenylalanine radical (DOPA•) in ß. The three-electron oxidation producing DOPA• occurs in Escherichia coli only if the ß is coexpressed with the NrdI activase encoded adjacently in the pathogen genome. The independence of this new RNR from transition metals, or the requirement for a single metal ion only transiently for activation, may afford the pathogens an even more potent countermeasure against transition metal-directed innate immunity.

Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment.

Background: Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR. Methods: We carried out a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created three versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0-10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose. Results: We randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group when compared with the HR group (mean difference -0.8, 95% confidence interval, -1.3 to -0.4, P < 0.01) and when compared with the HR+RMSTD group (difference -0.6, -1.1 to -0.1, P = 0.05). In all, 47.2% (42.7%-51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk. Conclusion: Misinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD when compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.

Rationalizing spatial exploration patterns of wild animals and humans through a temporal discounting framework.

Understanding the exploration patterns of foragers in the wild provides fundamental insight into animal behavior. Recent experimental evidence has demonstrated that path lengths (distances between consecutive turns) taken by foragers are well fitted by a power law distribution. Numerous theoretical contributions have posited that "Lévy random walks"-which can produce power law path length distributions-are optimal for memoryless agents searching a sparse reward landscape. It is unclear, however, whether such a strategy is efficient for cognitively complex agents, from wild animals to humans. Here, we developed a model to explain the emergence of apparent power law path length distributions in animals that can learn about their environments. In our model, the agent's goal during search is to build an internal model of the distribution of rewards in space that takes into account the cost of time to reach distant locations (i.e., temporally discounting rewards). For an agent with such a goal, we find that an optimal model of exploration in fact produces hyperbolic path lengths, which are well approximated by power laws. We then provide support for our model by showing that humans in a laboratory spatial exploration task search space systematically and modify their search patterns under a cost of time. In addition, we find that path length distributions in a large dataset obtained from free-ranging marine vertebrates are well described by our hyperbolic model. Thus, we provide a general theoretical framework for understanding spatial exploration patterns of cognitively complex foragers.

The Timing of Reward-Seeking Action Tracks Visually Cued Theta Oscillations in Primary Visual Cortex.

An emerging body of work challenges the view that primary visual cortex (V1) represents the visual world faithfully. Theta oscillations in the local field potential (LFP) of V1 have been found to convey temporal expectations and, specifically, to express the delay between a visual stimulus and the reward that it portends. We extend this work by showing how these oscillatory states in male, wild-type rats can even relate to the timing of a visually cued reward-seeking behavior. In particular, we show that, with training, high precision and accuracy in behavioral timing tracks the power of these oscillations and the time of action execution covaries with their duration. These LFP oscillations are also intimately related to spiking responses at the single-unit level, which themselves carry predictive timing information. Together, these observations extend our understanding of the role of cortical oscillations in timing generally and the role of V1 in the timing of visually cued behaviors specifically.SIGNIFICANCE STATEMENT Traditionally, primary visual cortex (V1) has been regarded as playing a purely perceptual role in stimulus-driven behaviors. Recent work has challenged that view by showing that theta oscillations in rodent V1 may come to convey timed expectations. Here, we show that these theta oscillations carry predictive information about timed reward-seeking actions, thus elucidating a behavioral role for theta oscillations in V1 and extending our understanding of the role of V1 in decision making.

Tauroursodeoxycholic acid binds to the G-protein site on light activated rhodopsin.

The heterotrimeric G-protein binding site on G-protein coupled receptors remains relatively unexplored regarding its potential as a new target of therapeutic intervention or as a secondary site of action by the existing drugs. Tauroursodeoxycholic acid bears structural resemblance to several compounds that were previously identified to specifically bind to the light-activated form of the visual receptor rhodopsin and to inhibit its activation of transducin. We show that TUDCA stabilizes the active form of rhodopsin, metarhodopsin II, and does not display the detergent-like effects of common amphiphilic compounds that share the cholesterol scaffold structure, such as deoxycholic acid. Computer docking of TUDCA to the model of light-activated rhodopsin revealed that it interacts using similar mode of binding to the C-terminal domain of transducin alpha subunit. The ring regions of TUDCA made hydrophobic contacts with loop 3 region of rhodopsin, while the tail of TUDCA is exposed to solvent. The results show that TUDCA interacts specifically with rhodopsin, which may contribute to its wide-ranging effects on retina physiology and as a potential therapeutic compound for retina degenerative diseases.

Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial.

PURPOSE: As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been associated with positive outcomes in cell and rodent models of aging. We hypothesized that dietary blueberry would improve mobility and cognition among older adults. METHODS: In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equivalent to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention. RESULTS: Significant supplement group by study visit interactions were observed on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031, ηp2 = 0.126) and reduced switch cost on a task-switching test (p = 0.033, ηp2 = 0.09) across study visits, relative to controls. However, no improvement in gait or balance was observed. CONCLUSIONS: These findings show that the addition of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition.

Health-related quality of life of survivors of childhood acute lymphoblastic leukemia: a systematic review.

PURPOSE: Acute lymphoblastic leukemia (ALL) survivors are the largest group of childhood cancer survivors; however, their risk for late effects is high. Cancer-related late effects have the potential to compromise health-related quality of life (HRQL) long into survivorship. None of the reviews so far have focused on ALL solely, but described HRQL for all childhood cancers. We aimed to identify ALL survivors at risk for poor HRQL and identify possible risk factors. METHOD: Following PRISMA guidelines, we performed a systematic review, searching published literature in Pubmed, PsycInfo, Embase, and the Cochrane database including all publications up to December 16, 2016. Two independent reviewers (JV and ER) screened eligible articles and assessed article quality. RESULTS: We found 31 studies representing 4356 survivors and 901 proxies. Thirteen studies found worse, eight found no difference, and three better, overall HRQL scores compared with healthy controls or norms. ALL survivors typically had better overall HRQL scores than survivors of other childhood cancers. Clinical variables (e.g., treatment received) were not consistently associated with HRQL; however, experiencing worse late effects was associated with lower HRQL. Survivor and parent socio-demographic factors and psychological factors such as resilience and depression were also associated with HRQL. CONCLUSION: ALL survivors appeared to have worse or equivalent HRQL compared with controls, but better HRQL than survivors of other cancer types. However, studies reported a wide variability in HRQL and potential risk factors for poor HRQL. Measuring ALL survivors' HRQL longitudinally and comprehensively assessing potential risk factors might identify future avenues to intervene early.

Clinical impact of the updated international postoperative pancreatic fistula definition in distal pancreatectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains the most common complication after distal pancreatectomy. The International Study Group on Pancreatic Surgery definition of POPF is used worldwide. Recently, an update of the definition was published. The aim of this study was to determine the clinical impact of the update. METHODS: An international retrospective validation study, including patients who underwent DP (2005 -2016) in 5 centers was performed. Distribution of complications amongst POPF grades were compared for the old and updated definition. RESULTS: In total, 1089 patients were included. The incidence of POPF decreased with the updated definition from 47% to 24% (P < 0.01), largely because a downgrade of grade A and grade B into biochemical leak. Comparable morbidity was seen in the old and updated 'no POPF group' (Clavien -Dindo 3 5% vs. 6% P = 0.320 and hospital stay (7 vs. 7 days P = 0.301). The change in definition of POPF grade B resulted in more Clavien -Dindo 3 (38% vs. 51%) P < 0.01) and longer hospital stay (9 [9 -13] vs. 9 days [7 -15] P < 0.01) in the updated `grade B group'. CONCLUSION: Applying the updated POPF definition showed improved discrimination between grades and should therefore be used to report POPF after DP.

A Case of Human Lassa Virus Infection With Robust Acute T-Cell Activation and Long-Term Virus-Specific T-Cell Responses.

A nurse who acquired Lassa virus infection in Togo in the spring of 2016 was repatriated to the United States for care at Emory University Hospital. Serial sampling from this patient permitted the characterization of several aspects of the innate and cellular immune responses to Lassa virus. Although most of the immune responses correlated with the kinetics of viremia resolution, the CD8 T-cell response was of surprisingly high magnitude and prolonged duration, implying prolonged presentation of viral antigens. Indeed, long after viremia resolution, there was persistent viral RNA detected in the semen of the patient, accompanied by epididymitis, suggesting the male reproductive tract as 1 site of antigen persistence. Consistent with the magnitude of acute T-cell responses, the patient ultimately developed long-term, polyfunctional memory T-cell responses to Lassa virus.

Health-related quality of life of children on treatment for acute lymphoblastic leukemia: A systematic review.

Children with acute lymphoblastic leukemia (ALL) undergo intense anticancer treatment. We systematically reviewed 22 studies evaluating 2,073 ALL patients' health-related quality of life (HRQL) and its clinical/demographic correlates during treatment. Overall HRQL was significantly reduced on treatment. Despite HRQL improvements over time, longitudinal studies reported a proportion of children continued to experience reduced HRQL after treatment completion. We found inconsistent associations between clinical/demographic factors and HRQL outcomes. Tentative evidence emerged for worse HRQL being associated with intensive phases of chemotherapy, corticosteroid therapy, experiencing greater toxicity, older age, and female sex. Longitudinal studies are needed to identify children at-risk of reduced HRQL.

Dietary supplementation with the polyphenol-rich açaí pulps (Euterpe oleracea Mart. and Euterpe precatoria Mart.) improves cognition in aged rats and attenuates inflammatory signaling in BV-2 microglial cells.

OBJECTIVES: The present study was carried out to determine if lyophilized açaí fruit pulp (genus, Euterpe), rich in polyphenols and other bioactive antioxidant and anti-inflammatory phytochemicals, is efficacious in reversing age-related cognitive deficits in aged rats. METHODS: The diets of 19-month-old Fischer 344 rats were supplemented for 8 weeks with 2% Euterpe oleracea (EO), Euterpe precatoria (EP), or a control diet. Rats were tested in the Morris water maze and then blood serum from the rats was used to assess inflammatory responses of BV-2 microglial cells. RESULTS: After 8 weeks of dietary supplementation with 2% EO or EP, rats demonstrated improved working memory in the Morris water maze, relative to controls; however, only the EO diet improved reference memory. BV-2 microglial cells treated with blood serum collected from EO-fed rats produced less nitric oxide (NO) than control-fed rats. Serum from both EO- and EP-fed rats reduced tumor necrosis factor-alpha (TNF-α). There is a relationship between performance in the water maze and the production of NO and TNF-α by serum-treated BV-2 cells, such that serum from rats with better performance was more protective against inflammatory signaling. DISCUSSION: Protection of memory during aging by supplementation of lyophilized açaí fruit pulp added to the diet may result from its ability to influence antioxidant and anti-inflammatory signaling.

Understanding the school experiences of children and adolescents with serious chronic illness: a systematic meta-review.

BACKGROUND: Serious chronic illness can have a detrimental effect on school attendance, participation and engagement, leaving affected students at risk of failing to meet their developmental potential. An improved understanding of factors that help to explain or mitigate this risk can help educators and health professionals deliver the most effective support. This meta-review critiqued the available evidence examining the link between six chronic illnesses (asthma, cancer, chronic kidney diseases, heart diseases, cystic fibrosis and gastrointestinal diseases) and children's and adolescents' school experiences and outcomes, as well as investigating the medical, school, psychosocial and sociodemographic factors that are linked to poorer or better school outcomes. METHODS: We searched CINAHL, Cochrane Database, EMBASE, ERIC, MEDLINE, ProQuest Theses and Dissertations, and PsycINFO (2000-2015). Systematic and narrative reviews, and meta-analyses, of original studies examining students' subjective school experiences and objective school outcomes were eligible. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria to critically appraise all systematic reviews. The Grading of Recommendations Assessment, Development, and Evaluation system guided our recommendations for practice and research. RESULTS: Eighteen reviews of 172 studies including more than 40 000 students were eligible. Therefore, we chose to conduct a meta-review to provide an overview of the literature on the relationship between chronic illness and school experiences and outcomes. We also explored the associated medical, school, psychosocial and sociodemographic factors affecting the relationship between illness and school experiences and outcomes. CONCLUSION: Students with chronic illness demonstrate mixed school experiences and outcomes that are often worse than students without chronic illness. Modifiable factors, such as students' engagement with school, may be novel yet appropriate targets of educational support to ensure that these students reach their full schooling potential.

Theta Oscillations in Visual Cortex Emerge with Experience to Convey Expected Reward Time and Experienced Reward Rate.

The primary visual cortex (V1) is widely regarded as faithfully conveying the physical properties of visual stimuli. Thus, experience-induced changes in V1 are often interpreted as improving visual perception (i.e., perceptual learning). Here we describe how, with experience, cue-evoked oscillations emerge in V1 to convey expected reward time as well as to relate experienced reward rate. We show, in chronic multisite local field potential recordings from rat V1, that repeated presentation of visual cues induces the emergence of visually evoked oscillatory activity. Early in training, the visually evoked oscillations relate to the physical parameters of the stimuli. However, with training, the oscillations evolve to relate the time in which those stimuli foretell expected reward. Moreover, the oscillation prevalence reflects the reward rate recently experienced by the animal. Thus, training induces experience-dependent changes in V1 activity that relate to what those stimuli have come to signify behaviorally: when to expect future reward and at what rate.

A Simple Network Architecture Accounts for Diverse Reward Time Responses in Primary Visual Cortex.

Many actions performed by animals and humans depend on an ability to learn, estimate, and produce temporal intervals of behavioral relevance. Exemplifying such learning of cued expectancies is the observation of reward-timing activity in the primary visual cortex (V1) of rodents, wherein neural responses to visual cues come to predict the time of future reward as behaviorally experienced in the past. These reward-timing responses exhibit significant heterogeneity in at least three qualitatively distinct classes: sustained increase or sustained decrease in firing rate until the time of expected reward, and a class of cells that reach a peak in firing at the expected delay. We elaborate upon our existing model by including inhibitory and excitatory units while imposing simple connectivity rules to demonstrate what role these inhibitory elements and the simple architectures play in sculpting the response dynamics of the network. We find that simply adding inhibition is not sufficient for obtaining the different distinct response classes, and that a broad distribution of inhibitory projections is necessary for obtaining peak-type responses. Furthermore, although changes in connection strength that modulate the effects of inhibition onto excitatory units have a strong impact on the firing rate profile of these peaked responses, the network exhibits robustness in its overall ability to predict the expected time of reward. Finally, we demonstrate how the magnitude of expected reward can be encoded at the expected delay in the network and how peaked responses express this reward expectancy. SIGNIFICANCE STATEMENT: Heterogeneity in single-neuron responses is a common feature of neuronal systems, although sometimes, in theoretical approaches, it is treated as a nuisance and seldom considered as conveying a different aspect of a signal. In this study, we focus on the heterogeneous responses in the primary visual cortex of rodents trained with a predictable delayed reward time. We describe under what conditions this heterogeneity can arise by self-organization, and what information it can convey. This study, while focusing on a specific system, provides insight onto how heterogeneity can arise in general while also shedding light onto mechanisms of reinforcement learning using realistic biological assumptions.

Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition.

The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders. SIGNIFICANCE STATEMENT: Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity.