Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Biology, Methodology or Chance? The Degree Distributions of Bipartite Ecological Networks

The distribution of the number of links per species, or degree distribution, is widely used as a summary of the topology of complex networks. Degree distributions have been studied in a range of ecological networks, including both mutualistic bipartite networks of plants and pollinators or seed dispersers and antagonistic bipartite networks of plants and their consumers. The shape of a degree distribution, for example whether it follows an exponential or power-law form, is typically taken to be indicative of the processes structuring the network. The skewed degree distributions of bipartite mutualistic and antagonistic networks are usually assumed to show that ecological or co-evolutionary processes constrain the relative numbers of specialists and generalists in the network. I show that a simple null model based on the principle of maximum entropy cannot be rejected as a model for the degree distributions in most of the 115 bipartite ecological networks tested here. The model requires knowledge of the number of nodes and links in the network, but needs no other ecological information. The model cannot be rejected for 159 (69%) of the 230 degree distributions of the 115 networks tested. It performed equally well on the plant and animal degree distributions, and cannot be rejected for 81 (70%) of the 115 plant distributions and 78 (68%) of the animal distributions. There are consistent differences between the degree distributions of mutualistic and antagonistic networks, suggesting that different processes are constraining these two classes of networks. Fit to the MaxEnt null model is consistently poor among the largest mutualistic networks. Potential ecological and methodological explanations for deviations from the model suggest that spatial and temporal heterogeneity are important drivers of the structure of these large networks

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Perineal discomfort in prostatic adenocarcinoma

We highlight the risk of missing a high-grade\ud (Gleason Grade 7/8) transition zone adenocarcinoma\ud in a patient presenting with perineal discomfort\ud on sitting

Operator theory and function theory in Drury-Arveson space and its quotients

The Drury-Arveson space $H^2_d$, also known as symmetric Fock space or the $d$-shift space, is a Hilbert function space that has a natural $d$-tuple of operators acting on it, which gives it the structure of a Hilbert module. This survey aims to introduce the Drury-Arveson space, to give a panoramic view of the main operator theoretic and function theoretic aspects of this space, and to describe the universal role that it plays in multivariable operator theory and in Pick interpolation theory.Comment: Final version (to appear in Handbook of Operator Theory); 42 page

Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults

BACKGROUND: Type 2 diabetes is associated with an increased risk for Alzheimer’s disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. // OBJECTIVE: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOE ɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance. // METHODS: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer’s Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOE ɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOE ɛ4 status. // RESULTS: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 . APOE ɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. // CONCLUSION: Overall, the findings suggest that IR and APOE ɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD

What Was I Thinking? Eye-Tracking Experiments Underscore the Bias that Architecture Exerts on Nuclear Grading in Prostate Cancer

We previously reported that nuclear grade assignment of prostate carcinomas is subject to a cognitive bias induced by the tumor architecture. Here, we asked whether this bias is mediated by the non-conscious selection of nuclei that “match the expectation” induced by the inadvertent glance at the tumor architecture. 20 pathologists were asked to grade nuclei in high power fields of 20 prostate carcinomas displayed on a computer screen. Unknown to the pathologists, each carcinoma was shown twice, once before a background of a low grade, tubule-rich carcinoma and once before the background of a high grade, solid carcinoma. Eye tracking allowed to identify which nuclei the pathologists fixated during the 8 second projection period. For all 20 pathologists, nuclear grade assignment was significantly biased by tumor architecture. Pathologists tended to fixate on bigger, darker, and more irregular nuclei when those were projected before kigh grade, solid carcinomas than before low grade, tubule-rich carcinomas (and vice versa). However, the morphometric differences of the selected nuclei accounted for only 11% of the architecture-induced bias, suggesting that it can only to a small part be explained by the unconscious fixation on nuclei that “match the expectation”. In conclusion, selection of « matching nuclei » represents an unconscious effort to vindicate the gravitation of nuclear grades towards the tumor architecture