• Energy Research
• CA close
• Neuroinformatics close
• McGill University close

Preformed gas bubbles can increase energy absorption from an ultrasound beam and therefore they have been proposed for an enhancer of ultrasound treatments. Although tissue temperature measurements performed in vivo using invasive thermocouple probes and MRI thermometry have demonstrated increased tissue temperature, the microscopic temperature distribution has not been investigated so far. In this study the transfer of heat between bubbles and tissue during focused ultrasound was simulated. Microbubble oscillations were simulated within a rat cortical microvascular network reconstructed from in vivo dual-photon microscopy images and the power density of these oscillations was used as an input term in the Pennes bioheat transfer equation. The temperature solution from the bioheat transfer equation was mapped onto vascular data to produce a three-dimensional temperature map. The results showed high temperatures near the bubbles and slow temperature rise in the tissue. Heating was shown to increase with increasing bubble frequency and insonation pressure, and showed a frequency-dependent peak. The goal of this research is to characterize the effect of various parameters on bubble-enhanced therapeutic ultrasound to allow better treatment planning. These results show that the induced temperature elevations have nonuniformities which may have a significant impact on the bio-effects of the exposure.

Normal males received amino acid mixtures designed to raise or lower tryptophan availability, and thus to raise or lower brain serotonin synthesis. They also received alcoholic or non-alcoholic drinks. The subjects were tested in the Taylor Competitive Reaction Time Task in which they competed against a (non-existent) partner in a reaction time task. The magnitude of electric shocks that the subjects were willing to give to their bogus partner was used as a measure of aggression. Lowered tryptophan levels and ingestion of alcohol were associated with increased aggression. Our data support the idea that low serotonin levels may be involved in the etiology of aggression. They suggest that subjects with low brain serotonin levels may be particularly susceptible to alcohol-induced violence.

Aldehyde dehydrogenase (ALDH) and catalase enzymatic activities in brain were assayed and compared to measures of alcohol consumption in two groups of animals screened and maintained on free-choice alcohol access under different conditions. In the first group of Long-Evans rats screened and maintained in home cages, mean alcohol intake was 3.49 g/kg/day with a range of 1.69-5.33 g/kg/day. When alcohol intake (g/kg), total ALDH, low K(m) ALDH, and catalase activities were entered in a multiple regression, a significant correlation of r = 0.51 (p < 0.05) was obtained. In the second group of rats consisting of Long-Evans, P, and NP rats screened using a drinkometer procedure, a multiple correlation between ALDH and catalase enzyme activities and alcohol intake of r = 0.42 (p < 0.05) was obtained. There was a strong relationship between the frequency of alcohol drinking bouts and the activities of catalase and ALDH (r = 0.68, p < 0.0001). The P rats had significantly higher catalase activities than either the NP or Long-Evans rats. The results of the present study confirmed earlier reports on the role of alcohol-metabolizing enzymes in the regulation of alcohol intake. The results also highlighted the fact that the activity of these alcohol-metabolizing enzymes may play a mediating role in patterns of alcohol intake displayed by animals selected for high and low alcohol drinking and also unselected animals.

Abstract The acetylcholine-like activity in the subcellular particles from narcotized rat and rabbit brain was assayed with the frog rectus preparation and found to be more than that extractable from the brains of normal animals. Chromatographic separation of this material showed that the zone identified with the butyrobetaine CoA esters contained most of the acetylcholine-like activity. Chemical analysis revealed the presence of mainly acetyl-1-carnitine in almost all the extracts prepared from narcotized brains. From other data presented, it was concluded that narcotics cause an accumulation of acetyl-1-carnityl CoA and trace amounts of related substances in the brain. This accumulation may have been caused by inhibition of their release from the subcellular particles.

GABA is one of the principal inhibitory neurotransmitters in the mammalian brain and an ever increasing wealth of information suggests that GABAergic mechanisms have a special role in the neurophysiology of anxiety. All of the most commonly used antianxiety drugs (the benzodiazepines, the barbiturates, ethanol) selectively enhance only GABA-mediated synaptic transmission. Furthermore, the relative affinities of pharmacologically active benzodiazepines for the benzodiazepine receptor correlate well with their ability to antagonize GABA-modulin (the endogenous inhibitor of GABA receptors) in vitro, as well as with their ability to potentiate GABA-mediated electrically evoked cortical inhibition in vivo. Finally, it is of interest for the neurophysiology of anxiety that repetitive stimulation of the recurrent inhibitory GABAergic pathway in the rat hippocampus leads to a remarkable reduction of the effectiveness of GABA; this elimination of GABAergic “inhibition” is counteracted by antianxiety drugs. On the basis of the above a neurophysiological model of anxiety is proposed.

Ethanol (ethyl alcohol) potentiates the inhibition of cortical neurons by γ-aminobutyric acid. This effect is specific, since ethanol does not potentiate inhibition by glycine, serotonin, or dopamine. These results have implications for alcoholism because (i) γ-aminobutyric acid mediates anxiolytic mechanisms, and (ii) anxiety is implicated in the etiology of alcoholism.

AbstractThe dismantling and elimination of excess neurons and their connections (pruning) is essential for brain development and may be aberrantly reactivated in some neurodegenerative diseases. Growing evidence implicates caspase‐mediated apoptotic and nonapoptotic cascades in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. It is the cleaved caspase substrates that are the effectors of synapse elimination. However, their identities, specific cleavage sites, and functional consequences of cleavage are largely unknown. An important gap in our knowledge is a comprehensive catalog of synapse‐specific or synapse‐enriched caspase targets. Traditional biochemical approaches have revealed only a small number of neuronal caspase targets. Instead, we utilized a gel‐based proteomics approach to enable the first global analysis of caspase‐mediated cleavage events in mammalian brain synapses, employing both an in vitro system with recombinant activated caspases and an in vivo model of ethanol‐induced neuronal apoptosis. Of the more than 70 putative cleavage substrates that were identified, 22 were previously known caspase substrates. Among the novel targets identified and validated by Western blot were the proton pump ATPase subunit ATP6V1B2 and the N‐ethylmaleimide‐sensitive fusion protein (NSF). Our work represents the first comprehensive, proteome‐wide screen for proteolytic targets of caspases in neuronal synapses. Our discoveries will have significance for both furthering basic understanding of roles of caspases in synaptic plasticity and synaptic loss in neurodegeneration, and on a more immediately practical level, may provide candidate biomarkers for measuring synapse loss in human disease states.

AbstractBackgroundPrenatal alcohol exposure (PAE) is associated with smaller regional and global brain volumes. In rats, gestational choline supplementation mitigates adverse developmental effects of ethanol exposure. Our recent randomized, double‐blind, placebo‐controlled maternal choline supplementation trial showed improved somatic and functional outcomes in infants at 6.5 and 12 months postpartum. Here, we examined whether maternal choline supplementation protected the newborn brain from PAE‐related volume reductions and, if so, whether these volume changes were associated with improved infant recognition memory.MethodsFifty‐two infants born to heavy‐drinking women who had participated in a choline supplementation trial during pregnancy underwent structural magnetic resonance imaging with a multi‐echo FLASH protocol on a 3T Siemens Allegra MRI (median age = 2.8 weeks postpartum). Subcortical regions were manually segmented. Recognition memory was assessed at 12 months on the Fagan Test of Infant Intelligence (FTII). We examined the effects of choline on regional brain volumes, whether choline‐related volume increases were associated with higher FTII scores, and the degree to which the regional volume increases mediated the effects of choline on the FTII.ResultsUsable MRI data were acquired in 50 infants (choline: n = 27; placebo: n = 23). Normalized volumes were larger in six of 12 regions in the choline than placebo arm (t ≥ 2.05, p ≤ 0.05) and were correlated with the degree of maternal choline adherence (β ≥ 0.28, p ≤ 0.04). Larger right putamen and corpus callosum were related to higher FTII scores (r = 0.36, p = 0.02) with a trend toward partial mediation of the choline effect on recognition memory.ConclusionsHigh‐dose choline supplementation during pregnancy mitigated PAE‐related regional volume reductions, with larger volumes associated with improved 12‐month recognition memory. These results provide the first evidence that choline may be neuroprotective against PAE‐related brain structural deficits in humans.

Prion protein inhibits Bax activation and Bax-mediated cell death in primary cultures of human neurons and in MCF-7 cells. To determine whether prion protein can protect against Bax-mediated cell death in vivo, wild-type, null and prion over-expressing mice were subjected to Bax-dependent ethanol induced neuronal apoptotic cell death and the brains were immunostained for active caspase-3 as a downstream marker of Bax activation. Bax activation occurs in all ethanol-injected mice independent of their genotype. A higher level of cell death is present in ethanol-injected null mice than in wild-type and prion over-expressing mice. We conclude that prion protein protects some, but not all neurons, against Bax-mediated cell death in this experimental paradigm.