Spinal cord plasticity in peripheral inflammatory pain

Inflammatory pain is a debilitating condition that can occur following tissue injury or inflammation and results in touch evoked pain (allodynia), exaggerated pain (hyperalgesia) and spontaneous pain, yet the neural plasticity underlying these symptoms is not fully understood. However, it is known that lamina I neurokinin 1 receptor expressing (NK1R+) spinal cord output neurons are crucial for the manifestation of inflammatory pain. There is also evidence that the afferent input to and the postsynaptic response of these neurons may be altered in inflammatory pain, which could be relevant for inflammatory pain hypersensitivity. Therefore, the aim of this thesis was to study inflammatory pain spinal plasticity mechanisms by investigating the synaptic input to lamina I NK1R+ neurons. In ex vivo spinal cord and dorsal root preparations from the rat, electrophysiological techniques were used to assess inflammation-induced changes in and pharmacological manipulation of the primary afferent drive to lamina I NK1R+ neurons. The excitatory input to lamina I NK1R+ neurons was examined and it was found that inflammation did not alter the relative distribution of the type of primary afferent input received and did not potentiate monosynaptic A δ or monosynaptic C-fibre input, the predominant input to these neurons. Spontaneous excitatory input was significantly elevated in the subset of neurons that received monosynaptic A δ-fibre input only, regardless of inflammation. It has recently been shown that the chemerin receptor 23 (ChemR23) represents a novel inflammatory pain target, whereby ChemR23 agonists can decrease inflammatory pain hypersensitivity, by a mechanism that involves the attenuation of potentiated spinal cord responses. This study has found that the ChemR23 agonist, chemerin, attenuated capsaicin potentiation of excitatory input to lamina I NK1R+ neurons and significantly reduced monosynaptic C-fibre input to a subset of these neurons in inflammatory pain. However, chemerin was without effect in non-potentiated conditions. In exploring potential inflammatory pain spinal plasticity mechanisms, I have investigated a phenomenon called activity-dependent slowing (ADS), whereby repetitive stimulation of C-fibres at frequencies of 1Hz or above results in a progressive slowing of action potential conduction velocity, which manifests as a progressive increase in response latency. This is proposed to limit nociceptive input to the spinal cord, thus regulating plasticity. Results demonstrate that inflammation significantly attenuated C-fibre ADS in isolated dorsal roots. Furthermore, ADS in monosynaptic C-fibre input to lamina I NK1R+ neurons was significantly reduced in inflammatory pain, which could facilitate nociceptive drive to these key spinal cord output neurons and promote inflammatory pain spinal cord plasticity. In conclusion, the major novel findings of this thesis are firstly, that chemerin can attenuate primary afferent input to lamina I NK1R+ neurons in potentiated conditions, which supports recent studies that suggest ChemR23 is a potential target for the development of new analgesics. Secondly, it was discovered that ADS in monosynaptic C-fibre inputs to lamina I NK1R+ neurons is altered in inflammatory pain, which could be relevant for inflammatory pain spinal plasticity. The findings presented in this thesis could contribute to the development of novel inflammatory pain treatments

Response of Mycorrhizal Diversity to Current Climatic Changes

Form and function of mycorrhizas as well as tracing the presence of the mycorrhizal fungi through the geological time scale are herein first addressed. Then mycorrhizas and plant fitness, succession, mycorrhizas and ecosystem function, and mycorrhizal resiliency are introduced. From this, four hypotheses are drawn: (1) mycorrhizal diversity evolved in response to changes in Global Climate Change (GCC) environmental drivers, (2) mycorrhizal diversity will be modified by present changes in GCC environmental drivers, (3) mycorrhizal changes in response to ecological drivers of GCC will in turn modify plant, community, and ecosystem responses to the same, and (4) Mycorrhizas will continue to evolve in response to present and future changes in GCC factors. The drivers of climate change examined here are: CO2 enrichment, temperature rise, altered precipitation, increased N-deposition, habitat fragmentation, and biotic invasion increase. These impact the soil-rhizosphere, plant and fungal physiology and/or ecosystem(s) directly and indirectly. Direct effects include changes in resource availability and change in distribution of mycorrhizas. Indirect effects include changes in below ground allocation of C to roots and changes in plant species distribution. GCC ecological drivers have been partitioned into four putative time frames: (1) Immediate (1–2 years) impacts, associated with ecosystem fragmentation and habitat loss realized through loss of plant-hosts and disturbance of the soil; (2) Short-term (3–10 year) impacts, resultant of biotic invasions of exotic mycorrhizal fungi, plants and pests, diseases and other abiotic perturbations; (3) Intermediate-term (11–20 year) impacts, of cumulative and additive effects of increased N (and S) deposition, soil acidification and other pollutants; and (4) Long-term (21–50+ year) impacts, where increased temperatures and CO2 will destabilize global rainfall patterns, soil properties and plant ecosystem resilience. Due to dependence on their host for C-supply, orchid mycorrhizas and all heterotrophic mycorrhizal groups will be immediately impacted through loss of habitat and plant-hosts. Ectomycorrhizal (ECM) associations will be the principal group subject to short-term impacts, along with Ericoid mycorrhizas occurring in high altitude or high latitude ecosystems. This is due to susceptibility (low buffer capacity of soils) of many of the ECM systems and that GCC is accentuated at high latitudes and altitudes. Vulnerable mycorrhizal types subject to intermediate-term GCC changes include highly specialized ECM species associated with forest ecosystems and finally arbuscular mycorrhizas (AM) associated with grassland ecosystems. Although the soils of grasslands are generally well buffered, the soils of arid lands are highly buffered and will resist even fairly long term GCC impacts, and thus these arid, largely AM systems will be the least affect by GCC. Once there are major perturbations to the global hydrological cycle that change rainfall patterns and seasonal distributions, no aspect of the global mycorrhizal diversity will remain unaffected

Reproducibility in the absence of selective reporting: An illustration from large‐scale brain asymmetry research

The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes