A neurophysiological and proteomic study of cognitive enhancing strategies

Improving cognitive function is a growing area of interest for pharmaceutical companies. With an ageing population, cognitive decline is becoming a greater problem. Understanding the physiological effects of nootropic drugs and the changes that occur during cognitive enhancement will enable the design of safer treatments to enhance cognition. In this thesis cognitive enhancing strategies are investigated using neurophysiological and proteomic approaches. The effects of two classes of putatively cognitive enhancing drugs on emergent network oscillatory activities in hippocampal slices are investigated. The effect of an enriched environment, which causes an improvement in cognitive function, on the expression level of proteins in the hippocampus is also investigated. The development of a new muscarinic acetylcholine receptor (mAChR) agonist that is selective for the M1 mAChR subtype, called 77-LH-281, has recently been achieved. 77-LH-281 binds to an allosteric site of the M1 mAChR which accounts for its increased selectivity over other mAChR agonists. This agonist causes gamma frequency oscillatory activity in hippocampal slices, a pattern of network activity that the in vivo equivalent of which is associated with cognitive processes. This gamma activity is dependent upon both excitatory and inhibitory networks. 77-LH-281 does not promote epileptiform-like activity in naïve slices as well as a range of models of epileptiform activity, unlike non-subtype selective mAChR agonists like oxotremorine-M. Oxotremorine-M changes the slow inter-ictal-like events following application of 4-AP and NBQX into continuous beta frequency oscillations. This action is not mediated by the M1 mAChR. Thus selective M¬1 mAChR display a preferable range of oscillatory activities compared to non-subtype selective mAChR agonists. Ampakines are a further class of nootropic drugs. Ampakines are positive modulators of AMPA-type glutamate receptors and they cause improvements in cognitive function of laboratory animals and humans. The ampakines investigated in this thesis are CX691, which increases the amplitude of currents through the AMPA receptor, and CX546, which increases the length of time the AMPA receptor is open. These ampakines do not induce oscillatory activity in naïve hippocampal slices, but they increase the frequency of inter-ictal-like epileptiform activity. CX546 also induces ictal-like activity in the 4-AP induced epileptiform event model. Ampakines may therefore promote epileptiform activity in individuals that are susceptible to epilepsy. Exposure to an enriched environment leads to improvements in cognitive performance. This behavioural change is mediated by changes at the level of the proteome. Exposure to an enriched environment changes the expression of many classes of proteins including signalling proteins and proteins that are involved in the structural changes that occur during cognitive enhancement. One of the proteins that significantly changes in expression is a protein that is associated with cognitive deficits, known as MeCP2. MeCP2 is a transcriptional repressor and increases in expression in the enriched environment. This thesis demonstrates the diversity of molecular, cellular and network level approaches that can be used to induce and investigate cognitive enhancement. A combination of these approaches enables the in vitro evaluation of current cognitive enhancing strategies and may lead to the the development of novel approaches to enhance cognitive function

A neurophysiological and proteomic study of cognitive enhancing strategies

Improving cognitive function is a growing area of interest for pharmaceutical companies. With an ageing population, cognitive decline is becoming a greater problem. Understanding the physiological effects of nootropic drugs and the changes that occur during cognitive enhancement will enable the design of safer treatments to enhance cognition. In this thesis cognitive enhancing strategies are investigated using neurophysiological and proteomic approaches. The effects of two classes of putatively cognitive enhancing drugs on emergent network oscillatory activities in hippocampal slices are investigated. The effect of an enriched environment, which causes an improvement in cognitive function, on the expression level of proteins in the hippocampus is also investigated. The development of a new muscarinic acetylcholine receptor (mAChR) agonist that is selective for the M1 mAChR subtype, called 77-LH-281, has recently been achieved. 77-LH-281 binds to an allosteric site of the M1 mAChR which accounts for its increased selectivity over other mAChR agonists. This agonist causes gamma frequency oscillatory activity in hippocampal slices, a pattern of network activity that the in vivo equivalent of which is associated with cognitive processes. This gamma activity is dependent upon both excitatory and inhibitory networks. 77-LH-281 does not promote epileptiform-like activity in naïve slices as well as a range of models of epileptiform activity, unlike non-subtype selective mAChR agonists like oxotremorine-M. Oxotremorine-M changes the slow inter-ictal-like events following application of 4-AP and NBQX into continuous beta frequency oscillations. This action is not mediated by the M1 mAChR. Thus selective M¬1 mAChR display a preferable range of oscillatory activities compared to non-subtype selective mAChR agonists. Ampakines are a further class of nootropic drugs. Ampakines are positive modulators of AMPA-type glutamate receptors and they cause improvements in cognitive function of laboratory animals and humans. The ampakines investigated in this thesis are CX691, which increases the amplitude of currents through the AMPA receptor, and CX546, which increases the length of time the AMPA receptor is open. These ampakines do not induce oscillatory activity in naïve hippocampal slices, but they increase the frequency of inter-ictal-like epileptiform activity. CX546 also induces ictal-like activity in the 4-AP induced epileptiform event model. Ampakines may therefore promote epileptiform activity in individuals that are susceptible to epilepsy. Exposure to an enriched environment leads to improvements in cognitive performance. This behavioural change is mediated by changes at the level of the proteome. Exposure to an enriched environment changes the expression of many classes of proteins including signalling proteins and proteins that are involved in the structural changes that occur during cognitive enhancement. One of the proteins that significantly changes in expression is a protein that is associated with cognitive deficits, known as MeCP2. MeCP2 is a transcriptional repressor and increases in expression in the enriched environment. This thesis demonstrates the diversity of molecular, cellular and network level approaches that can be used to induce and investigate cognitive enhancement. A combination of these approaches enables the in vitro evaluation of current cognitive enhancing strategies and may lead to the the development of novel approaches to enhance cognitive function.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Delta Directions Consortium (DDC): Summary of Collaborative Pathways

The Delta Directions Consortium is an interdisciplinary network of individuals, academic institutions, non-profit organizations, and foundations that work together to create positive social change in the multi-state Mississippi Delta Region. Goals include improving public health and promoting socioeconomic development. The Consortium is not an independent non-profit organization but, rather, an alliance of partners committed to collaborative and innovative problem-solving. This document provides a summary of pathways for partners in the Delta Directions Consortium, with emphasis on substantive topics and projects. It should be read as a living document to frame ideas and approaches that will be adapted in response to the needs and interests of core partners and diverse stakeholders

RQ-00201894: A motilin receptor agonist causing long-lasting facilitation of human gastric cholinergically-mediated contractions

Under a Creative Commons licenseNT, MT, MS and TY are employees of RaQualia. GJS received funding from RaQualia for JB to conduct the human stomach studies. Open Access funded by Japanese Pharmacological Societ

Changes in neuromuscular structure and functions of human colon during ageing are region-dependent

Objective: To determine if human colonic neuromuscular functions decline with increasing age.Design: Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35–91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35–60 years) groups.Results: With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI ), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthaseimmunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/gtissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon.Conclusion: In ascending not descending colon, ageing impairs cholinergic function

Snake prices and crocodile appetites: Aquatic wildlife supply and demand on Tonle Sap Lake, Cambodia

Commercial trade is a major driver of over-exploitation of wild species, but the pattern of demand and how it responds to changes in supply is poorly understood. Here we explore the markets for snakes from Tonle Sap Lake in Cambodia to evaluate future exploitation scenarios, identify entry points for conservation and, more generally, to illustrate the value of multi-scale analysis of markets to traded wildlife conservation. In Cambodia, the largest driver of snake exploitation is the domestic trade in snakes as crocodile food. We estimate that farmed crocodiles consume between 2.7 and 12.2 million snakes per year. The market price for crocodiles has been in decline since 2003, which, combined with rising prices for their food, has led to a reduced frequency of feeding and closure of small farms. The large farms that generate a disproportionate amount of the demand for snakes continue to operate in anticipation of future market opportunities, and preferences for snakes could help maintain demand if market prices for crocodiles rise to pre 2003 levels. In the absence of a sustained demand from crocodile farms, it is also possible that alternative markets will develop, such as one for human snack food. The demand for snakes, however, also depends on the availability of substitute resources, principally fish. The substitutability and low price elasticity of demand offers a relatively sustainable form of consumerism. Given the nature of these market drivers, addressing consumer preferences and limiting the protection of snakes to their breeding season are likely to be the most effective tools for conservation. This study highlights the importance of understanding the structure of markets and the behaviour of consumer demand prior to implementing regulations on wildlife hunting and trade

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans

Forum: issues and reflections on ethics and writing assessment

Open access article. Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license (CC BY-NC-ND 4.0) appliesWe hope this special issue adds to the body of knowledge created by the writing studies community with respect to the opportunities that can be created when assessment is seen in terms of the creation of opportunity structure. This hope is accompanied by a reminder of our strength as we annually encounter approximately 48.9 million students in public elementary and secondary schools 20.6 million students in postsecondary institutions (Snyder & Dillow, 2015). Our influence is remarkable as we touch the lives of many, one student at a time.Ye

Radiative transfer with scattering for domain-decomposed 3D MHD simulations of cool stellar atmospheres

We present the implementation of a radiative transfer solver with coherent scattering in the new BIFROST code for radiative magneto-hydrodynamical (MHD) simulations of stellar surface convection. The code is fully parallelized using MPI domain decomposition, which allows for large grid sizes and improved resolution of hydrodynamical structures. We apply the code to simulate the surface granulation in a solar-type star, ignoring magnetic fields, and investigate the importance of coherent scattering for the atmospheric structure. A scattering term is added to the radiative transfer equation, requiring an iterative computation of the radiation field. We use a short-characteristics-based Gauss-Seidel acceleration scheme to compute radiative flux divergences for the energy equation. The effects of coherent scattering are tested by comparing the temperature stratification of three 3D time-dependent hydrodynamical atmosphere models of a solar-type star: without scattering, with continuum scattering only, and with both continuum and line scattering. We show that continuum scattering does not have a significant impact on the photospheric temperature structure for a star like the Sun. Including scattering in line-blanketing, however, leads to a decrease of temperatures by about 350\,K below log tau < -4. The effect is opposite to that of 1D hydrostatic models in radiative equilibrium, where scattering reduces the cooling effect of strong LTE lines in the higher layers of the photosphere. Coherent line scattering also changes the temperature distribution in the high atmosphere, where we observe stronger fluctuations compared to a treatment of lines as true absorbers.Comment: A&A, in pres