Housing Assistance Among Patients with Cancer: SEER-Medicare U.S. Department of Housing and Urban Development Data Linkage.

BACKGROUND: Lack of stable and affordable housing is an important social determinant of health. Federal housing assistance may buffer against housing vulnerabilities among low-income households, but research examining the association of housing assistance and cancer care has been limited. We introduce a new linkage of SEER-Medicare and Housing and Urban Development (HUD) administrative data. METHODS: Individuals enrolled in HUD public and assisted housing programs 2006-2021 were linked with cancer diagnoses 2006-2019 identified in the SEER-Medicare data from 16 states using Match*Pro probabilistic linkage software. HUD administrative data include timing and type of housing assistance and verified household income. Medicare administrative data are available through 2020. RESULTS: A total of 335,490 unique individuals who received housing assistance matched to SEER-Medicare data at any point in time, including 156,794 that recieved housing assistance around the time of their diagnosis (at least 6 months prior to diagnosis until 6 months after diagnosis or death). A total of 63,251 persons with housing assistance at the time of their diagnosis were aged 66 years and older and continuously enrolled in Medicare Parts A and B fee-for-service, 12,035 with lung, 8,866 with breast, 7,261 with colorectal, and 4,703 with prostate cancer. CONCLUSIONS: This novel data linkage will be available through the National Cancer Institute and can be used to explore the ways in which housing assistance is associated with cancer diagnosis, care, and outcomes, including the role of housing assistance status in potentially reducing or contributing to inequities across racialized and ethnic groups.

Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.

Highly glycosylated MUC1 mediates high affinity L-selectin binding at the human endometrial surface.

BACKGROUND: Sialyl-Lewis X/L-selectin high affinity binding interactions between transmembrane O-glycosylated mucins proteins and the embryo have been implicated in implantation processes within the human reproductive system. However, the adhesive properties of these mucins at the endometrial cell surface are difficult to resolve due to known discrepancies between in vivo models and the human reproductive system and a lack of sensitivity in current in vitro models. To overcome these limitations, an in vitro model of the human endometrial epithelial was interrogated with single molecule force spectroscopy (SMFS) to delineate the molecular configurations of mucin proteins that mediate the high affinity L-selectin binding required for human embryo implantation. RESULTS: This study reveals that MUC1 contributes to both the intrinsic and extrinsic adhesive properties of the HEC-1 cellular surface. High expression of MUC1 on the cell surface led to a significantly increased intrinsic adhesion force (148 pN vs. 271 pN, p < 0.001), whereas this adhesion force was significantly reduced (271 pN vs. 118 pN, p < 0.001) following siRNA mediated MUC1 ablation. Whilst high expression of MUC1 displaying elevated glycosylation led to strong extrinsic (> 400 pN) L-selectin binding at the cell surface, low expression of MUC1 with reduced glycosylation resulted in significantly less (≤200 pN) binding events. CONCLUSIONS: An optimal level of MUC1 together with highly glycosylated decoration of the protein is critical for high affinity L-selectin binding. This study demonstrates that MUC1 contributes to cellular adhesive properties which may function to facilitate trophoblast binding to the endometrial cell surface through the L-selectin/sialyl-Lewis x adhesion system subsequent to implantation.

Activation of D1 receptors affects human reactivity and flexibility to valued cues.

Reward-predicting cues motivate goal-directed behavior, but in unstable environments humans must also be able to flexibly update cue-reward associations. While the capacity of reward cues to trigger motivation ('reactivity') as well as flexibility in cue-reward associations have been linked to the neurotransmitter dopamine in humans, the specific contribution of the dopamine D1 receptor family to these behaviors remained elusive. To fill this gap, we conducted a randomized, placebo-controlled, double-blind pharmacological study testing the impact of three different doses of a novel D1 agonist (relative to placebo) on reactivity to reward-predicting cues (Pavlovian-to-instrumental transfer) and flexibility of cue-outcome associations (reversal learning). We observed that the impact of the D1 agonist crucially depended on baseline working memory functioning, which has been identified as a proxy for baseline dopamine synthesis capacity. Specifically, increasing D1 receptor stimulation strengthened Pavlovian-to-instrumental transfer in individuals with high baseline working memory capacity. In contrast, higher doses of the D1 agonist improved reversal learning only in individuals with low baseline working memory functioning. Our findings suggest a crucial and baseline-dependent role of D1 receptor activation in controlling both cue reactivity and the flexibility of cue-reward associations.

Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Unique contributions of parvalbumin and cholinergic interneurons in organizing striatal networks during movement.

Striatal parvalbumin (PV) and cholinergic interneurons (CHIs) are poised to play major roles in behavior by coordinating the networks of medium spiny cells that relay motor output. However, the small numbers and scattered distribution of these cells have hindered direct assessment of their contribution to activity in networks of medium spiny neurons (MSNs) during behavior. Here, we build on recent improvements in single-cell calcium imaging combined with optogenetics to test the capacity of PVs and CHIs to affect MSN activity and behavior in mice engaged in voluntary locomotion. We find that PVs and CHIs have unique effects on MSN activity and dissociable roles in supporting movement. PV cells facilitate movement by refining the activation of MSN networks responsible for movement execution. CHIs, in contrast, synchronize activity within MSN networks to signal the end of a movement bout. These results provide new insights into the striatal network activity that supports movement.

Drug Addiction: Mechanisms of Nicotine Dependence Unmasked by Gene Editing.

New gene editing technologies are enabling exploration of previously intractable features of genetic risk for drug addiction. A recent study using this technology reveals new insights into how a mutation linked to tobacco dependence influences the addictive properties of nicotine.

α5 nAChR modulation of the prefrontal cortex makes attention resilient.

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated. In the present studies, we used RNA interference to knockdown the α5 nAChR subunit in the PFC of adult rats. We provide evidence that through its contribution to cholinergic modulation of cholinergic modulation of neurons in the PFC, the α5 nAChR plays a specific role in the recovery of attention task performance following distraction. Our combined data reveal the potent ability of this subunit to modulate the PFC and cognitive functions controlled by this brain region that are impaired in disease.

Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection.

The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection.SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.

Modeling Late-Summer Distribution of Golden Eagles (Aquila chrysaetos) in the Western United States.

Increasing development across the western United States (USA) elevates concerns about effects on wildlife resources; the golden eagle (Aquila chrysaetos) is of special concern in this regard. Knowledge of golden eagle abundance and distribution across the western USA must be improved to help identify and conserve areas of major importance to the species. We used distance sampling and visual mark-recapture procedures to estimate golden eagle abundance from aerial line-transect surveys conducted across four Bird Conservation Regions in the western USA between 15 August and 15 September in 2006-2010, 2012, and 2013. To assess golden eagle-habitat relationships at this scale, we modeled counts of golden eagles seen during surveys in 2006-2010, adjusted for probability of detection, and used land cover and other environmental factors as predictor variables within 20-km2 sampling units randomly selected from survey transects. We found evidence of positive relationships between intensity of use by golden eagles and elevation, solar radiation, and mean wind speed, and of negative relationships with the proportion of landscape classified as forest or as developed. The model accurately predicted habitat use observed during surveys conducted in 2012 and 2013. We used the model to construct a map predicting intensity of use by golden eagles during late summer across our ~2 million-km2 study area. The map can be used to help prioritize landscapes for conservation efforts, identify areas where mitigation efforts may be most effective, and identify regions for additional research and monitoring. In addition, our map can be used to develop region-specific (e.g., state-level) density estimates based on the latest information on golden eagle abundance from a late-summer survey and aid designation of geographic management units for the species.

Nicotinic receptor subtypes differentially modulate glutamate release in the dorsal medial striatum.

The dorsal medial striatum is a crucial part of the neural network that subserves dynamic, goal-directed behaviors. Functional output of this nucleus is shaped, in part, by the influence of glutamatergic inputs. Striatal cholinergic systems have the capacity to modulate these excitatory inputs through presynaptic nicotinic acetylcholine receptors (nAChRs); however, the individual contribution of the two major nicotinic receptor subtypes, α4ß2 and α7, to such modulation is not well characterized. In the present experiments, glutamate biosensors were used to monitor nAChR-dependent glutamate release with high temporal precision in the dorsal medial striatum of rats. Both α4ß2 and α7 nAChRs were found to potently modulate glutamate release; however the two receptor subtypes do so in strikingly different ways. α7 nAChRs appear to enhance release from glutamatergic terminals. In contrast, α4ß2 nAChRs act as a brake on glutamate release via an interaction with local dopaminergic inputs and D2 receptors. Combined, the present data reveal the capacity of local striatal cholinergic signaling to dynamically modulate excitatory inputs through nAChRs.

What do phasic cholinergic signals do?

In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (3) How can cognitive state influence transient occurrence? (4) Why do cholinergic transients peak at around the time of reward delivery? (5) Is there evidence of cholinergic transients in humans? We conclude by outlining future research studies necessary to more fully understand the role of cholinergic transients in mediating cue detection.

Cortical cholinergic signaling controls the detection of cues.

The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.

MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function.

RATIONALE: Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia. OBJECTIVE: We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments. METHODS: MAM animals' capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task. RESULTS: MAM animals' basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge. CONCLUSIONS: The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior.

Deterministic functions of cortical acetylcholine.

Traditional descriptions of the basal forebrain cholinergic projection system to the cortex have focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing. Through presynaptic receptors expressed on cholinergic terminals, thalamocortical and corticocortical projections can evoke brief cholinergic release events. These acetylcholine (ACh) release events occur on a fast, sub-second to seconds-long time scale ('transients'). In rats performing a task requiring the detection of cues as well as the report of non-cue events cholinergic transients mediate the detection of cues specifically in trials that involve a shift from a state of monitoring for cues to cue-directed responding. Accordingly, ill-timed cholinergic transients, generated using optogenetic methods, force false detections in trials without cues. We propose that the evidence is consistent with the hypothesis that cholinergic transients reduce detection uncertainty in such trials. Furthermore, the evidence on the functions of the neuromodulatory component of cholinergic neurotransmission suggests that higher levels of neuromodulation favor staying-on-task over alternative action. In other terms, higher cholinergic neuromodulation reduces opportunity costs. Evidence indicating a similar integration of other ascending projection systems, including noradrenergic and serotonergic systems, into cortical circuitry remains sparse, largely because of the limited information about local presynaptic regulation and the limitations of current techniques in measuring fast and transient neurotransmitter release events in these systems.

Clinical outcomes from the CDC's Colorectal Cancer Screening Demonstration Program.

BACKGROUND: Colorectal cancer remains the second leading cause of cancer-related deaths among US men and women. Screening rates have been slow to increase, and disparities in screening remain. METHODS: To address the disparity in screening for this high burden but largely preventable disease, the Centers for Disease Control and Prevention (CDC) designed and established a 4-year Colorectal Cancer Screening Demonstration Program (CRCSDP) in 2005 for low-income, under-insured or uninsured men and women aged 50 to 64 years in 5 participating US program sites. In this report, the authors describe the design of the CRCSDP and the overall clinical findings and screening test performance characteristics, including the positive fecal occult blood testing (FOBT) rate; the rates of polyp, adenoma, and cancer detection with FOBTs and colonoscopies; and the positive predicative value for polyps, adenomas, and cancers. RESULTS: In total, 5233 individuals at average risk and increased risk were screened for colorectal cancer across all 5 sites, including 44% who underwent screening FOBT and 56% who underwent screening colonoscopy. Overall, 77% of all individuals screened were women. The FOBT positivity rate was 10%. Results from all screening or diagnostic colonoscopies indicated that 75% had negative results and required a repeat screening colonoscopy in 10 years, 16% had low-risk adenomas and required surveillance colonoscopy in 5 to 10 years, 8% had high-risk adenomas and required surveillance colonoscopy in 3 years, and 0.6% had invasive cancers. CONCLUSIONS: This report documents the successes and challenges in implementing the CDC's CRCSDP and describes the clinical outcomes of this 4-year initiative, the patterns in program uptake and test choice, and the comparative test performance characteristics of FOBT versus colonoscopy. Patterns in final outcomes from the follow-up of positive screening tests were consistent with national registry data.

Prefrontal cholinergic mechanisms instigating shifts from monitoring for cues to cue-guided performance: converging electrochemical and fMRI evidence from rats and humans.

We previously reported involvement of right prefrontal cholinergic activity in veridical signal detection. Here, we first recorded real-time acetylcholine release in prefrontal cortex (PFC) during specific trial sequences in rats performing a task requiring signal detection as well as rejection of nonsignal events. Cholinergic release events recorded with subsecond resolution ("transients") were observed only during signal-hit trials, not during signal-miss trials or nonsignal events. Moreover, cholinergic transients were not observed for consecutive hits; instead they were limited to signal-hit trials that were preceded by factual or perceived nonsignal events ("incongruent hits"). This finding suggests that these transients mediate shifts from a state of perceptual attention, or monitoring for cues, to cue-evoked activation of response rules and the generation of a cue-directed response. Next, to determine the translational significance of the cognitive operations supporting incongruent hits we used a version of the task previously validated for use in research in humans and blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging. Incongruent hits activated a region in the right rostral PFC (Brodmann area 10). Furthermore, greater prefrontal activation was correlated with faster response times for incongruent hits. Finally, we measured tissue oxygen in rats, as a proxy for BOLD, and found prefrontal increases in oxygen levels solely during incongruent hits. These cross-species studies link a cholinergic response to a prefrontal BOLD activation and indicate that these interrelated mechanisms mediate the integration of external cues with internal representations to initiate and guide behavior.