Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Derivation of consistent hard rock (1000<Vs<3000 m/s) GMPEs from surface and down-hole recordings: Analysis of KiK-net data

A key component in seismic hazard assessment is the estimation of ground motion for hard rock sites, either for applications to installations built on this site category, or as an input motion for site response computation. Empirical ground motion prediction equations (GMPEs) are the traditional basis for estimating ground motion while VS30 is the basis to account for site conditions. As current GMPEs are poorly constrained for VS30 larger than 1000 m/s, the presently used approach for estimating hazard on hard rock sites consists of “host-to-target” adjustment techniques based on VS30 and κ0 values. The present study investigates alternative methods on the basis of a KiK-net dataset corresponding to stiff and rocky sites with 500 < VS30 < 1350 m/s. The existence of sensor pairs (one at the surface and one in depth) and the availability of P- and S-wave velocity profiles allow deriving two “virtual” datasets associated to outcropping hard rock sites with VS in the range [1000, 3000] m/s with two independent corrections: 1/down-hole recordings modified from within motion to outcropping motion with a depth correction factor, 2/surface recordings deconvolved from their specific site response derived through 1D simulation. GMPEs with simple functional forms are then developed, including a VS30 site term. They lead to consistent and robust hard-rock motion estimates, which prove to be significantly lower than host-to-target adjustment predictions. The difference can reach a factor up to 3–4 beyond 5 Hz for very hard-rock, but decreases for decreasing frequency until vanishing below 2 Hz

Estimates of CO2 from fires in the United States: implications for carbon management

<p>Abstract</p> <p>Background</p> <p>Fires emit significant amounts of CO₂to the atmosphere. These emissions, however, are highly variable in both space and time. Additionally, CO₂emissions estimates from fires are very uncertain. The combination of high spatial and temporal variability and substantial uncertainty associated with fire CO₂emissions can be problematic to efforts to develop remote sensing, monitoring, and inverse modeling techniques to quantify carbon fluxes at the continental scale. Policy and carbon management decisions based on atmospheric sampling/modeling techniques must account for the impact of fire CO₂emissions; a task that may prove very difficult for the foreseeable future. This paper addresses the variability of CO₂emissions from fires across the US, how these emissions compare to anthropogenic emissions of CO₂and Net Primary Productivity, and the potential implications for monitoring programs and policy development.</p> <p>Results</p> <p>Average annual CO₂emissions from fires in the lower 48 (LOWER48) states from 2002–2006 are estimated to be 213 (± 50 std. dev.) Tg CO₂yr^-1and 80 (± 89 std. dev.) Tg CO₂yr^-1in Alaska. These estimates have significant interannual and spatial variability. Needleleaf forests in the Southeastern US and the Western US are the dominant source regions for US fire CO₂emissions. Very high emission years typically coincide with droughts, and climatic variability is a major driver of the high interannual and spatial variation in fire emissions. The amount of CO₂emitted from fires in the US is equivalent to 4–6% of anthropogenic emissions at the continental scale and, at the state-level, fire emissions of CO₂can, in some cases, exceed annual emissions of CO₂from fossil fuel usage.</p> <p>Conclusion</p> <p>The CO₂released from fires, overall, is a small fraction of the estimated average annual Net Primary Productivity and, unlike fossil fuel CO₂emissions, the pulsed emissions of CO₂during fires are partially counterbalanced by uptake of CO₂by regrowing vegetation in the decades following fire. Changes in fire severity and frequency can, however, lead to net changes in atmospheric CO₂and the short-term impacts of fire emissions on monitoring, modeling, and carbon management policy are substantial.</p

Behavioral and Autonomic Responses to Acute Restraint Stress Are Segregated within the Lateral Septal Area of Rats

Background: The Lateral Septal Area (LSA) is involved with autonomic and behavior responses associated to stress. In rats, acute restraint (RS) is an unavoidable stress situation that causes autonomic (body temperature, mean arterial pressure (MAP) and heart rate (HR) increases) and behavioral (increased anxiety-like behavior) changes in rats. The LSA is one of several brain regions that have been involved in stress responses. The aim of the present study was to investigate if the neurotransmission blockade in the LSA would interfere in the autonomic and behavioral changes induced by RS. Methodology/Principal Findings: Male Wistar rats with bilateral cannulae aimed at the LSA, an intra-abdominal datalogger (for recording internal body temperature), and an implanted catheter into the femoral artery (for recording and cardiovascular parameters) were used. They received bilateral microinjections of the non-selective synapse blocker cobalt chloride (CoCl2, 1 mM / 100 nL) or vehicle 10 min before RS session. The tail temperature was measured by an infrared thermal imager during the session. Twenty-four h after the RS session the rats were tested in the elevated plus maze (EPM). Conclusions/Significance: Inhibition of LSA neurotransmission reduced the MAP and HR increases observed during RS. However, no changes were observed in the decrease in skin temperature and increase in internal body temperature observed during this period. Also, LSA inhibition did not change the anxiogenic effect induced by RS observed 24 h later in the EPM. The present results suggest that LSA neurotransmission is involved in the cardiovascular but not the temperatur

Phylogenetic Relationships and Evolutionary Patterns of the Order Collodaria (Radiolaria)

Collodaria are the only group of Radiolaria that has a colonial lifestyle. This group is potentially the most important plankton in the oligotrophic ocean because of its large biomass and the high primary productivity associated with the numerous symbionts inside a cell or colony. The evolution of Collodaria could thus be related to the changes in paleo-productivity that have affected organic carbon fixation in the oligotrophic ocean. However, the fossil record of Collodaria is insufficient to trace their abundance through geological time, because most collodarians do not have silicified shells. Recently, molecular phylogeny based on nuclear small sub-unit ribosomal DNA (SSU rDNA) confirmed Collodaria to be one of five orders of Radiolaria, though the relationship among collodarians is still unresolved because of inadequate taxonomic sampling. Our phylogenetic analysis has revealed four novel collodarian sequences, on the basis of which collodarians can be divided into four clades that correspond to taxonomic grouping at the family level: Thalassicollidae, Collozoidae, Collosphaeridae, and Collophidae. Comparison of the results of our phylogenetic analyses with the morphological characteristics of each collodarian family suggests that the first ancestral collodarians had a solitary lifestyle and left no silica deposits. The timing of events estimated from molecular divergence calculations indicates that naked collodarian lineages first appeared around 45.6 million years (Ma) ago, coincident with the diversification of diatoms in the pelagic oceans. Colonial collodarians appeared after the formation of the present ocean circulation system and the development of oligotrophic conditions in the equatorial Pacific (ca. 33.4 Ma ago). The divergence of colonial collodarians probably caused a shift in the efficiency of primary production during this period

The Proprioceptive Map of the Arm Is Systematic and Stable, but Idiosyncratic

Visual and somatosensory signals participate together in providing an estimate of the hand's spatial location. While the ability of subjects to identify the spatial location of their hand based on visual and proprioceptive signals has previously been characterized, relatively few studies have examined in detail the spatial structure of the proprioceptive map of the arm. Here, we reconstructed and analyzed the spatial structure of the estimation errors that resulted when subjects reported the location of their unseen hand across a 2D horizontal workspace. Hand position estimation was mapped under four conditions: with and without tactile feedback, and with the right and left hands. In the task, we moved each subject's hand to one of 100 targets in the workspace while their eyes were closed. Then, we either a) applied tactile stimulation to the fingertip by allowing the index finger to touch the target or b) as a control, hovered the fingertip 2 cm above the target. After returning the hand to a neutral position, subjects opened their eyes to verbally report where their fingertip had been. We measured and analyzed both the direction and magnitude of the resulting estimation errors. Tactile feedback reduced the magnitude of these estimation errors, but did not change their overall structure. In addition, the spatial structure of these errors was idiosyncratic: each subject had a unique pattern of errors that was stable between hands and over time. Finally, we found that at the population level the magnitude of the estimation errors had a characteristic distribution over the workspace: errors were smallest closer to the body. The stability of estimation errors across conditions and time suggests the brain constructs a proprioceptive map that is reliable, even if it is not necessarily accurate. The idiosyncrasy across subjects emphasizes that each individual constructs a map that is unique to their own experiences

When Right Feels Left: Referral of Touch and Ownership between the Hands

Feeling touch on a body part is paradigmatically considered to require stimulation of tactile afferents from the body part in question, at least in healthy non-synaesthetic individuals. In contrast to this view, we report a perceptual illusion where people experience “phantom touches” on a right rubber hand when they see it brushed simultaneously with brushes applied to their left hand. Such illusory duplication and transfer of touch from the left to the right hand was only elicited when a homologous (i.e., left and right) pair of hands was brushed in synchrony for an extended period of time. This stimulation caused the majority of our participants to perceive the right rubber hand as their own and to sense two distinct touches – one located on the right rubber hand and the other on their left (stimulated) hand. This effect was supported by quantitative subjective reports in the form of questionnaires, behavioral data from a task in which participants pointed to the felt location of their right hand, and physiological evidence obtained by skin conductance responses when threatening the model hand. Our findings suggest that visual information augments subthreshold somatosensory responses in the ipsilateral hemisphere, thus producing a tactile experience from the non-stimulated body part. This finding is important because it reveals a new bilateral multisensory mechanism for tactile perception and limb ownership

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Nicotinic receptors

Regulation of normal or abnormal behaviour is critically controlled by the central serotonergic systems. Recent evidence has suggested that serotonin (5-HT) neurotransmission dysfunction contributes to a variety of pathological conditions, including depression, anxiety, schizophrenia and Parkinson’s disorders. There is also a great amount of evidence indicating that 5-HT signalling may affect the reinforcing properties of drugs of abuse by the interaction and modulation of dopamine (DA) function. This chapter is focused on one of the more addictive drugs, nicotine. It is widely recognised that the effects of nicotine are strongly associated with the stimulatory action it exhibits on mesolimbic DAergic function. We outline the role of 5-HT and its plethora of receptors, focusing on 5-HT2 subtypes with relation to their involvement in the neurobiology of nicotine addiction. We also explore the novel pharmacological approaches using 5-HT agents for the treatment of nicotine dependence. Compelling evidence shows that 5-HT2C receptor agonists may be possible therapeutic targets for smoking cessation, although further investigation is required.peer-reviewe