Cognitive Control of Escape Behaviour

When faced with potential predators, animals instinctively decide whether there is a threat they should escape from, and also when, how, and where to take evasive action. While escape is often viewed in classical ethology as an action that is released upon presentation of specific stimuli, successful and adaptive escape behaviour relies on integrating information from sensory systems, stored knowledge, and internal states. From a neuroscience perspective, escape is an incredibly rich model that provides opportunities for investigating processes such as perceptual and value-based decision-making, or action selection, in an ethological setting. We review recent research from laboratory and field studies that explore, at the behavioural and mechanistic levels, how elements from multiple information streams are integrated to generate flexible escape behaviour

Limitations of Counseling and Testing in CDC\u27s HIV Prevention Efforts

To the Editor: We were delighted to see that our colleagues at the Centers for Disease Control and Prevention (CDC) had read our article (Darrow et al., 1998a) and responded (Wolitski and Doll, 1999). Their criticisms of our cross-sectional study of 51 HIV-infected men who have sex with men (MSM) and live in South Beach are welcomed and appreciated. In this brief reply, we continue the dialogue by addressing their concerns and recommending an appropriate course of action

Defective synapse maturation and enhanced synaptic plasticity in Shank2 Δex7(-/-) mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7(-/-) mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7(-/-) mice. Minimal stimulation experiments reveal that Shank2 Δex7(-/-) mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Δex6-7(-/-) mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs

Impact of HIV Counseling and Testing on HIV-Infected Men who have Sex with Men: The South Beach Health Survey

The impact of HIV counseling and testing on sexual risk-taking and related behaviors reported by HIV-infected men who have sex with men (MSM) was examined in a cross-sectional study conducted among a representative sample of residents living in a resort area. Participants provided specimens of oral mucosal transudate for HIV-antibody testing, were interviewed in their homes, and completed a self-administered questionnaire. Specimens were tested by modified ELISA and, if repeatedly positive, confirmed by Western blot. Of 205 men enrolled, 51 (24.9%) tested positive for antibody to HIV. All 51 had been counseled and tested for antibody to HIV-1 (median = 4 tests); 37 (74%) of 50 reported that their most recent test was positive. Twenty (39.2%) said they had engaged in unprotected insertive anal intercourse in the past year; 15 (29.4%) engaged in unprotected insertive anal intercourse with partners who may have been susceptible to HIV infection. Men who reported that their last HIV-antibody test was positive were three times more likely to have engaged in unprotected insertive anal intercourse in the past year (45.9%) as those who did not know they were infected with HIV (15.4%). Counseling and testing is ineffective as a measure for promoting behavior change among HIV-positive MSM in South Beach. More effective social and behavioral interventions must be developed, implemented, and evaluated

Cell-type-specific modulation of feedback inhibition by serotonin in the hippocampus

Midbrain raphe nuclei provide strong serotonergic projections to the hippocampus, in which serotonin (5-HT) exerts differential effects mediated by multiple 5-HT receptor subtypes. The functional relevance of this diversity of information processing is poorly understood. Here we show that serotonin via 5-HT(1B) heteroreceptors substantially reduces synaptic excitation of cholecystokinin-expressing interneurons in area CA1 of the rat hippocampus, in contrast to parvalbumin-expressing basket cells. The reduction is input specific, affecting only glutamatergic synaptic transmission originating from CA1 pyramidal cells. As a result, serotonin selectively decreases feedback inhibition via 5-HT(1B) receptor activation and subsequently increases the integration time window for spike generation in CA1 pyramidal cells. Our data imply an important role for serotonergic modulation of GABAergic action in subcortical control of hippocampal output

Cannabinoid type 2 receptors mediate a cell type-specific self-inhibition in cortical neurons

Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB1R and CB2R). In the central nervous system endocannabinoids are produced in an activity-dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell-autonomous slow self-inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long-lasting hyperpolarization of the membrane potential, rendering the cells less excitable. Different endocannabinoid receptors and effector mechanisms have been described underlying SSI in different cell types and brain areas. Here, we investigate SSI in neurons of layer 2/3 in the somatosensory cortex. High-frequency bursts of action potentials induced SSI in pyramidal cells (PC) and regular spiking non-pyramidal cells (RSNPC), but not in fast-spiking interneurons (FS). In RSNPCs the hyperpolarization was accompanied by a change in input resistance due to the activation of G protein-coupled inward-rectifying K+ (GIRK) channels. A CB2R-specific agonist induced the long-lasting hyperpolarization, whereas preincubation with a CB2R-specific inverse agonist suppressed SSI. Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB1R-deficient but abolished in CB2R-deficient mice. Taken together, we describe an additional SSI mechanism in which the activity-induced release of endocannabinoids activates GIRK channels via CB2Rs. These findings expand our knowledge about cell type-specific differential neuronal cannabinoid receptor signaling and suggest CB2R-selective compounds as potential therapeutic approaches

Clinicopathological correlations of mesenteric fibrosis and evaluation of a novel biomarker for fibrosis detection in small bowel neuroendocrine neoplasms

PURPOSE: Mesenteric fibrosis (MF) in small intestinal neuroendocrine neoplasms (SINENs) is often associated with significant morbidity and mortality. The detection of MF is usually based on radiological criteria, but no previous studies have attempted a prospective, multidimensional assessment of mesenteric desmoplasia to determine the accuracy of radiological measurements. There is also a lack of non-invasive biomarkers for the detection of image-negative MF. METHODS: A multidimensional assessment of MF incorporating radiological, surgical and histological parameters was performed in a prospective cohort of 34 patients with SINENs who underwent primary resection. Pre-operative blood samples were collected in 20 cases to evaluate a set of five profibrotic circulating transcripts-the "fibrosome"-that is included as an "omic" component of the NETest. RESULTS: There was a significant correlation between radiological and surgical assessments of MF (p < 0.05). However, there were several cases of image-negative MF. The NETest-fibrosome demonstrated an accuracy of 100% for the detection of microscopic MF. CONCLUSIONS: The detection of MF by radiological criteria has limitations. The NETest-fibrosome is a promising biomarker for fibrosis detection and further validation of these results would be needed in larger, multicentre studies

Neuroligin 1 is dynamically exchanged at postsynaptic sites

Neuroligins are postsynaptic cell adhesion molecules that associate with presynaptic neurexins. Both factors form a transsynaptic connection, mediate signaling across the synapse, specify synaptic functions, and play a role in synapse formation. Neuroligin dysfunction impairs synaptic transmission, disrupts neuronal networks, and is thought to participate in cognitive diseases. Here we report that chemical treatment designed to induce long-term potentiation or long-term depression (LTD) induces neuroligin 1/3 turnover, leading to either increased or decreased surface membrane protein levels, respectively. Despite its structural role at a crucial transsynaptic position, GFP-neuroligin 1 leaves synapses in hippocampal neurons over time with chemical LTD-induced neuroligin internalization depending on an intact microtubule cytoskeleton. Accordingly, neuroligin 1 and its binding partner postsynaptic density protein-95 (PSD-95) associate with components of the dynein motor complex and undergo retrograde cotransport with a dynein subunit. Transgenic depletion of dynein function in mice causes postsynaptic NLG1/3 and PSD-95 enrichment. In parallel, PSD lengths and spine head sizes are significantly increased, a phenotype similar to that observed upon transgenic overexpression of NLG1 (Dahlhaus et al., 2010). Moreover, application of a competitive PSD-95 peptide and neuroligin 1 C-terminal mutagenesis each specifically alter neuroligin 1 surface membrane expression and interfere with its internalization. Our data suggest the concept that synaptic plasticity regulates neuroligin turnover through active cytoskeleton transport