Individual differences in delay discounting and nicotine self-administration in rats

Delay discounting—a behavioral measure of impulsivity defined as a tendency to prefer a small, immediate reward over a larger reward delayed in time—has been extensively linked with tobacco smoking. However, the causal direction of this relationship remains unclear. One possibility is that delay discounting may be a marker for an underlying vulnerability to nicotine reinforcement—a possibility which can be isolated using an animal model. In the current study, we investigated whether indifference points derived using an adjustable delay procedure of delay discounting predicted several indices of nicotine reinforcement in rats, including rate of acquisition of nicotine self-administration, break point reached on a progressive ratio schedule of reinforcement, or a shift in the dose-response curve. Stable indifference points were assessed for 63 male Sprague-Dawley rats, and extreme groups of highly impulsive (HI; n=15) and low impulsive (LI; n=11) rats were selected to self-administer nicotine. Rats responded by nose poking for infusions of 0.03 mg/kg nicotine during 1 hour daily sessions. After a 20 session acquisition period, rats completed 3 4-hour progressive ratio sessions, during which the response requirement was increased after each infusion earned. This was followed by 3 1-hour fixed ratio sessions at each of 3 nicotine doses, presented in ascending order (0.015, 0.03, and 0.09 mg/kg). All but one rat (HI group) acquired stable nicotine self-administration; however, no group differences in rate of acquisition were observed. HI and LI rats did not differ in their responses on a progressive ratio schedule or infusions earned at any dose of nicotine, although a significant dose-response effect was observed overall. Indifference points reassessed after self-administration were highly correlated with original indifference points, and mean indifference points for each group at the second assessment did not differ significantly from baseline assessment. These results suggest that delay discounting is a highly reliable measure, but may not be a predictive marker for increased vulnerability to nicotine self-administration in rats

Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain

<p>Abstract</p> <p>Background</p> <p>Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.</p> <p>Results</p> <p>Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists.</p> <p>Conclusions</p> <p>The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state.</p

p38 MAPK, microglial signaling, and neuropathic pain

Accumulating evidence over last several years indicates an important role of microglial cells in the pathogenesis of neuropathic pain. Signal transduction in microglia under chronic pain states has begun to be revealed. We will review the evidence that p38 MAPK is activated in spinal microglia after nerve injury and contributes importantly to neuropathic pain development and maintenance. We will discuss the upstream mechanisms causing p38 activation in spinal microglia after nerve injury. We will also discuss the downstream mechanisms by which p38 produces inflammatory mediators. Taken together, current data suggest that p38 plays a critical role in microglial signaling under neuropathic pain conditions and represents a valuable therapeutic target for neuropathic pain management

Neuroimaging revolutionizes therapeutic approaches to chronic pain

An understanding of how the brain changes in chronic pain or responds to pharmacological or other therapeutic interventions has been significantly changed as a result of developments in neuroimaging of the CNS. These developments have occurred in 3 domains : (1) Anatomical Imaging which has demonstrated changes in brain volume in chronic pain; (2) Functional Imaging (fMRI) that has demonstrated an altered state in the brain in chronic pain conditions including back pain, neuropathic pain, and complex regional pain syndromes. In addition the response of the brain to drugs has provided new insights into how these may modify normal and abnormal circuits (phMRI or pharmacological MRI); (3) Chemical Imaging (Magnetic Resonance Spectroscopy or MRS) has helped our understanding of measures of chemical changes in chronic pain. Taken together these three domains have already changed the way in which we think of pain – it should now be considered an altered brain state in which there may be altered functional connections or systems and a state that has components of degenerative aspects of the CNS

Anticoagulant rodenticides on our public and community lands: spatial distribution of exposure and poisoning of a rare forest carnivore.

Anticoagulant rodenticide (AR) poisoning has emerged as a significant concern for conservation and management of non-target wildlife. The purpose for these toxicants is to suppress pest populations in agricultural or urban settings. The potential of direct and indirect exposures and illicit use of ARs on public and community forest lands have recently raised concern for fishers (Martes pennanti), a candidate for listing under the federal Endangered Species Act in the Pacific states. In an investigation of threats to fisher population persistence in the two isolated California populations, we investigate the magnitude of this previously undocumented threat to fishers, we tested 58 carcasses for the presence and quantification of ARs, conducted spatial analysis of exposed fishers in an effort to identify potential point sources of AR, and identified fishers that died directly due to AR poisoning. We found 46 of 58 (79%) fishers exposed to an AR with 96% of those individuals having been exposed to one or more second-generation AR compounds. No spatial clustering of AR exposure was detected and the spatial distribution of exposure suggests that AR contamination is widespread within the fisher's range in California, which encompasses mostly public forest and park lands Additionally, we diagnosed four fisher deaths, including a lactating female, that were directly attributed to AR toxicosis and documented the first neonatal or milk transfer of an AR to an altricial fisher kit. These ARs, which some are acutely toxic, pose both a direct mortality or fitness risk to fishers, and a significant indirect risk to these isolated populations. Future research should be directed towards investigating risks to prey populations fishers are dependent on, exposure in other rare forest carnivores, and potential AR point sources such as illegal marijuana cultivation in the range of fishers on California public lands

Population Densities and Disease Surveys of Wild Pigs in the Coast Ranges of Central and Northern California

In 1994 and 1995, 233 different wild pigs were captured during population research at seven research sites focused primarily in the coastal regions of central and northern California. Mark-resight data and information on wild pig movements were used to assess wild pig population densities at those sites. Population densities ranged from 1.01 wild pigs/km2 in Mendocino County in 1994 to 3.32 wild pigs/km2 in Santa Clara County in 1995. Comparisons of population densities between years at three research sites suggested that wild pig populations increased in 1995 in response to favorable forage conditions after the wet fall and winter of 1994-95. Serum samples collected from 462 wild pigs at 28 different sites were screened for exposure to brucellosis and pseudorabies. Preliminary results were that seropositive results for brucellosis were noted at only three sites, whereas no animals were confirmed seropositive for pseudorabies. Although analyses of these two diseases are continuing, test results for trichinellosis, toxoplasmosis, and sylvatic plague reinforce previous warnings to hunters and consumers that sanitary handling and cooking of wild swine meat are warranted

Patterns of Natural and Human-Caused Mortality Factors of a Rare Forest Carnivore, the Fisher (Pekania pennanti) in California.

Wildlife populations of conservation concern are limited in distribution, population size and persistence by various factors, including mortality. The fisher (Pekania pennanti), a North American mid-sized carnivore whose range in the western Pacific United States has retracted considerably in the past century, was proposed for threatened status protection in late 2014 under the United States Endangered Species Act by the United States Fish and Wildlife Service in its West Coast Distinct Population Segment. We investigated mortality in 167 fishers from two genetically and geographically distinct sub-populations in California within this West Coast Distinct Population Segment using a combination of gross necropsy, histology, toxicology and molecular methods. Overall, predation (70%), natural disease (16%), toxicant poisoning (10%) and, less commonly, vehicular strike (2%) and other anthropogenic causes (2%) were causes of mortality observed. We documented both an increase in mortality to (57% increase) and exposure (6%) from pesticides in fishers in just the past three years, highlighting further that toxicants from marijuana cultivation still pose a threat. Additionally, exposure to multiple rodenticides significantly increased the likelihood of mortality from rodenticide poisoning. Poisoning was significantly more common in male than female fishers and was 7 times more likely than disease to kill males. Based on necropsy findings, suspected causes of mortality based on field evidence alone tended to underestimate the frequency of disease-related mortalities. This study is the first comprehensive investigation of mortality causes of fishers and provides essential information to assist in the conservation of this species

Review of \u3ci\u3eUrochloa\u3c/i\u3e Breeder’s Toolbox with the Theory of Change and Stage Gate System Approach

Livestock production in the global south is at crossroads as there is a demand to increase Animal Source Foods to address hunger and pressure to lighten the environmental footprint often associated with livestock production. To satisfy both needs, the use of technologies that improve animal performance, while reducing land use and net Greenhouse Gas emissions produced by animals is essential. One of such technologies are Urochloa forage grasses. Urochloa forage grasses are well known for their rusticity and their ability to grow in soils of low fertility and high aluminum content. These characteristics allow Urochloa to grow in areas temporally or spatially less suitable for crop production, but also have made ruminants production profitable in areas that would not be otherwise. However, productivity and sustainability of ruminant production in these areas is likely to fall within the next decade due to climate change unless action is taken. Despite these known benefits of Urochloa forage species, breeding programs have long delayed initiation due to apomixes and differences in ploidy. In the mid-1980s, the development of suitable sexual germplasm allowed crossings, and therefore favoured the emergence of breeding programs. In recent decades, several advances in biology, molecular biology, phenotyping, population genetics, genomics and transcriptomics have generated a plethora of information that ought to be integrated for its use in a single breeding toolbox. We use the Theory of Change and Stage-Gate systems approach to review these advances in research and the utility of the current and future available tools. Further, we address the remaining lack of information, thus bridging the knowledge gap and enabling us to maximize the genetic gain in the different Urochloa breeding programs. In this way, we identify breeding bottlenecks and help to pinpoint priorities for Urochloa research and development

Tensile Forces and Shape Entropy Explain Observed Crista Structure in Mitochondria

A model is presented from which the observed morphology of the inner mitochondrial membrane can be inferred as minimizing the system's free energy. Besides the usual energetic terms for bending, surface area, and pressure difference, our free energy includes terms for tension that we believe to be exerted by proteins and for an entropic contribution due to many dimensions worth of shapes available at a given energy. In order to test the model, we measured the structural features of mitochondria in HeLa cells and mouse embryonic fibroblasts using 3D electron tomography. Such tomograms reveal that the inner membrane self-assembles into a complex structure that contains both tubular and flat lamellar crista components. This structure, which contains one matrix compartment, is believed to be essential to the proper functioning of mitochondria as the powerhouse of the cell. We find that tensile forces of the order of 10 pN are required to stabilize a stress-induced coexistence of tubular and flat lamellar cristae phases. The model also predicts \Deltap = -0.036 \pm 0.004 atm and \sigma=0.09 \pm 0.04 pN/nm

Book reviews

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45119/1/10943_2005_Article_BF01533201.pd