Why Can't Rodents Vomit? A Comparative Behavioral, Anatomical, and Physiological Study

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed. © 2013 Horn et al

Somatostatin Neurons in Prefrontal Cortical Microcircuits in Schizophrenia

Certain cognitive functions, including working memory, are impaired in individuals with schizophrenia. These cognitive impairments are key predictors of functional outcomes in this patient population, but there are no available therapeutic options to ameliorate these impairments. Only postmortem studies of the brain can reveal alterations in the cortical circuitry in schizophrenia that could underlie these cognitive disturbances and inform therapeutic intervention. Proper working memory function requires robust resistance to distracting information, and it appears that working memory deficits in schizophrenia reflect, at least in part, heightened susceptibility to distractors. The capacity for working memory generally, and especially for filtering out distracting information, is heavily dependent on activity in the dorsolateral prefrontal cortex (DLPFC). Convergent lines of evidence suggest that within the DLPFC, dendritic inhibition, provided from GABA neurons expressing the neuropeptide somatostatin (SST), is crucial for mediating distractor resistance in the DLPFC. The DLPFC, relative to other cortical regions, is enriched for SST mRNA, supporting the idea that SST neurons contribute to a distractor-resistant circuit. In schizophrenia, SST mRNA levels are markedly lower in the DLPFC, suggesting that impairment of these neurons in the disorder render these individuals more susceptible to distractors during working memory. Here, this dissertation work elucidates the basis for these differences in mRNA levels. In the first chapter, we find that higher SST in the DLPFC relative to the primary visual cortex reflects a greater proportion of SST neurons in the DLPFC, rather than SST levels per neuron. In contrast, in the second chapter, we find that deficits in SST mRNA in the DLPFC of schizophrenia primarily reflect lower gene expression per neuron without a deficit in neuron density. Finally, in the third chapter, we find that SST neurons exhibit lower levels of key GABA synthesizing enzymes in schizophrenia, indicating that these neurons have an impaired capacity to provide inhibition. The results of this dissertation reveal the nature of SST neuron disturbances in the DLPFC in schizophrenia, inform the putative impact of these alterations in the context of working memory, and offer insight for novel therapeutic interventions aimed at ameliorating the cognitive burden in the disorder

Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia

Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having "an orchestra without a conductor." Kraepelin further speculated that this "conductor" was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development

Near-Enantiopure Trimerization of 9-Ethynylphenanthrene on a Chiral Metal Surface

Enantioselectivity in heterogeneous catalysis strongly depends on the chirality transfer between catalyst surface and all reactants, intermediates, and the product along the reaction pathway. Herein we report the first enantioselective on-surface synthesis of molecular structures from an initial racemic mixture and without the need of enantiopure modifier molecules. The reaction consists of a trimerization via an unidentified bonding motif of prochiral 9-ethynylphenanthrene (9-EP) upon annealing to 500 K on the chiral Pd-3-terminated PdGa{111} surfaces into essentially enantiopure, homochiral 9-EP propellers. The observed behavior strongly contrasts the reaction of 9-EP on the chiral Pd-1-terminated PdGa{111} surfaces, where 9-EP monomers that are in nearly enantiopure configuration, dimerize without enantiomeric excess. Our findings demonstrate strong chiral recognition and a significant ensemble effect in the PdGa system, hence highlighting the huge potential of chiral intermetallic compounds for enantioselective synthesis and underlining the importance to control the catalytically active sites at the atomic level

Esophagus and stomach area measures.

<p><b>A)</b> Abdominal esophagus circumference/total esophagus length (cm). <b>B)</b> Abdominal esophagus length/total esophagus length. <b>C)</b> Percentage of stomach area to the left of vertical division. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone-0060537-g003" target="_blank">Figure 3</a> for a diagram showing location of these measures. * = p<0.05, planned contrast, a rodent species compared to all emetic species. Data represent mean ± SEM.</p

Behavioral test chambers.

<p><b>A)</b> Floor surface areas for chambers used for behavioral testing in different rodent species. Dashed lines indicate the locations of quadrants used to score locomotion during video playback. <b>B)</b> Larger chamber used to test nutria and beaver. All test chambers had a clear glass floor and video recordings of the ventral surface of animals were collected by reflection in a mirror (45° angle). This design is based on taste reactivity testing, which is focused on the recording of mouth movements in laboratory rodents <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Flynn1" target="_blank">[80]</a>.</p

The <i>in situ</i> brainstem preparation for musk shrews, mice, and rats.

<p>Animals were deeply anesthetized, decerebrated, and perfused with artificial blood. Recordings included the phrenic nerve activity, esophagus and mouth contraction force, and shoulder displacement. Electrocardiogram (ECG) was recorded from pins placed in the lateral edges of the preparation. Perfusion pressure was measured with a pressure tranducer located close to tip of the aorta perfusion catheter. The location of vagus nerve electrical stimulation is also shown. This preparation is adapted from Paton and colleagues <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Smith2" target="_blank">[28]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Paton1" target="_blank">[30]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Pickering1" target="_blank">[36]</a>.</p

Representative recordings of the mouth movement, esophagus movement, and phrenic nerve activity from the mouse (C57BL6), rat (Sprague-Dawley), and musk shrew in the <i>in situ</i> brainstem preparation.

<p>Vertical dashed lines indicate the start of the contraction of the esophagus after resiniferatoxin (RTX) was perfused through the brainstem (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone-0060537-g004" target="_blank">Fig. 4</a>). Plots show 15 s pre-event versus 15 s post-event (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone-0060537-g012" target="_blank">Fig. 12</a> for group averages). Mouth and esophageal recordings indicate force (g), with positive deflections showing opening of the mouth and shortening of the esophagus. Lines and event marks above each trace indicate events detected by computer software (DataView; <a href="http://www.st-andrews.ac.uk/~wjh/dataview/" target="_blank">http://www.st-andrews.ac.uk/~wjh/dataview/</a>).</p