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We examined patterns of Canadian Institute for Health Research (CIHR) funding on autism spectrum disorder (ASD) research. From 1999 to 2013, CIHR funded 190 ASD grants worth $48 million. Biomedical research received 43% of grants (46% of dollars), clinical research 27% (41%), health services 10% (7%), and population health research 8% (3%). The greatest number of grants was given in 2009, but 2003 saw the greatest amount. Funding is clustered in a handful of provinces and institutions, favouring biomedical research and disfavouring behavioural interventions, adaptation, and institutional response. Preference for biomedical research may be due to the detriment of clinical research.

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Adult male quail show high levels of aromatase activity in the preoptic area-hypothalamus (POA-HYP), which parallels the high number of aromatase-immunoreactive cells and elevated mRNA concentrations detected in this brain region by in situ hybridisation. Interestingly, females display considerably lower aromatase activity than males but have almost equal numbers of aromatase-immunoreactive cells and express similar levels of aromatase mRNA. Aromatase activity in the male POA-HYP can be rapidly regulated by calcium-dependent phosphorylations, in the absence of changes in enzyme concentration. In the present study, we investigated whether aromatase activity is differentially regulated by phosphorylations in males and females. A linear increase in accumulation of aromatisation products was observed in both sexes as a function of time but the rate of conversion was slower in females. Saturation analysis confirmed the lower maximum velocities (V(max) ) in females but indicated a similar affinity (K(m) ) in both sexes. Aromatase activity in females reacted differentially to manipulations of intracellular calcium. In particular, chelating calcium with ethylene glycol tetraacetic acid (EGTA) resulted in a larger increase of enzymatic activity in males than in females, especially in the presence of ATP. A differential reaction to kinase inhibitors was also observed between males and females (i.e. a larger increase in aromatase activity in females than in males after exposure to specific inhibitors). These findings suggest that the nature of aromatase is conserved between the sexes, although the control of its activity by calcium appears to be different. Additional characterizations of intracellular calcium in both sexes would therefore be appropriate to better understand aromatase regulation.

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The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.

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Decreased intake and weight loss are among the side effects frequently reported with chronic selective serotonin reuptake inhibitor (SSRI) use in both humans and animals. In an earlier study, we documented that paroxetine administered for several weeks induced a weight loss of greater than 10% in some male Sprague-Dawley rats (Pharmacol. Biochem. Behav. 63 (1999) 435). As a follow-up to that work, we investigated in this study whether such treatment influenced dietary macronutrient selection. Animals were first habituated to foods containing principally either proteins, fats, or carbohydrates in a self-selection paradigm, after which they were implanted intraperitoneally with osmotic minipumps that delivered either paroxetine (7.5 mg/kg/day) or vehicle (50:50 ethanol:water) for 28 days; food intake and weight changes were documented during this period. No acute effects of the drug were apparent. By the fifth day of treatment, significant differences in weight gain between groups were observed and thereafter generally maintained for the remainder of the study, with animals receiving paroxetine showing about an 8% decrease in weight gain overall. Carbohydrate and fat intakes were significantly reduced, whereas preference was unchanged in fats and proteins and initially decreased in carbohydrates; in the latter, this pattern reversed and exceeded vehicle animals for the second half of the study. Several hypotheses are discussed with respect to specific and nonspecific effects of paroxetine on feeding and macronutrient selection.

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The chronic unpredictable mild stress (CMS) is a paradigm developed in animals to model the relatively minor and unanticipated irritants that lead to a state of anhedonia in some individuals. However, the effectiveness of CMS is sometimes difficult to establish, for which unique strain sensitivities has been attributed as one contributing factor. These considerations led us to design the present study, which was an investigation of the corticosterone response to CMS in two outbred rat strains--Sprague-Dawley and Long Evans. Animals were exposed to one of two conditions--control or CMS--for 3 weeks during which body weight and fecal count were regularly monitored. At the end of this period, blood was sampled at a variety of time intervals following induction of a brief restraint stressor. First, a significant effect of CMS on corticosterone levels was evident at time 0 (prior to the application of the acute restraint stressor) in both strains. Second, the typical quadratic pattern of stressor-elicited fluctuations in this measure was similar in both Sprague-Dawley and Long Evans rats, with consistently elevated levels for the first hour following exposure to the acute stressor; near baseline values were observed at 2 h. However, only in the Long Evans strain were CMS related values much less than that observed in the control group after restraint stress. Third, both strains showed a reduced weight gain in the CMS groups relative to control groups. Fourth, spleen and adrenal weights were similar across all groups. Fifth, fecal counts remained stable across weeks of treatment in all groups with the exception of the Long Evans rats exposed to CMS; in this group, average counts were systematically reduced over the treatment period. We conclude that a history of chronic stress significantly blunts corticosterone levels in Long Evans but not Sprague-Dawley rats following exposure to an acute stressor. Physiological indices however are less influenced by this experience, at least when the exposure is limited to 3 weeks.

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Thresholds determined from the frequency of pulses and the current for rewarding brain stimulation were obtained from rats with lateral hypothalamic electrodes. The threshold, defined as the frequency or current corresponding to one-half the maximum response rate, was interpolated from reward summation functions. Daily trials of both ascending and descending sequences of frequency and current yielded no significant difference between order of presentation. While there was more variability in the maximum response rates across the sessions, neither frequency- nor current-based threshold evaluations yielded significant rate effects. Our findings suggest that the threshold procedure is generally not influenced by the sequence of delivery of stimulus values and, thus, may be regarded as a reliable measure of the reinforcing properties of brain-stimulation reward.

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Double-pulse tests were used to estimate the refractory periods and anatomical linkage of the reward-relevant fibers that course between the lateral preoptic and lateral hypothalamic areas. In the 1st study, pairs of conditioning and test pulses were delivered to each site, and the interval between pulses varied; recovery from refractoriness was similar at both sites, with the curves generally rising from 0.6 to 2.0 ms. In the 2nd study, the pairs of pulses were delivered to both sites. Six of 7 rats showed evidence of axonal collision, with estimates of conduction velocity that ranged from 0.48 to 8.95 m/s across rats. These results suggest that a wide spectrum of fiber types characterizes the reward-relevant axons that course uninterruptedly between these 2 regions.

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Given the putative role of the lateral preoptic area as a primary contributor of the cell bodies of origin of the descending pathway linking a subset of lateral hypothalamic and ventral tegmental area reward neurons, the distribution of self-stimulation sites in this structure was mapped in 22 animals using moveable electrodes and threshold procedures. Ninety-seven electrode sites were evaluated with placements ranging from just rostral to the midline convergence of the anterior commissure back to the transition zone between the lateral preoptic and lateral hypothalamic areas; of these, roughly 2/3 supported self-stimulation which was widely observed throughout the lateral preoptic area and medial forebrain bundle. In general, self-stimulation thresholds obtained from lateral sites were most stable, and progressively so approaching more caudal regions. Examination of the slopes of the period/current trade-off functions revealed a tendency for higher values in lateral and caudal sites; in contrast, dorsoventral excursions did not influence these estimates. Taken together, these data provide support for the notion that the substrate for brain-stimulation reward in the lateral preoptic area has a relatively homogeneous distribution that is more diffusely organized than that found in reward sites activated further caudally in the medial forebrain bundle.

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This experiment investigated the existence of a direct anatomical connection between lateral preoptic and ventral tegmental areas that mediate brain stimulation reward using the behavioral adaptation of the collision test. This test is a double-pulse, two-electrode technique based on the axonal conduction failure that occurs when two separate sites in the same axon bundle are concurrently stimulated. This anatomical arrangement is inferred from the shape of the function relating the effectiveness of double-pulse stimulation to the interval between pulses. In this study, nine rats with a total of 44 pairs of sites were examined. In two pairs only was there a profile suggestive of an axonal collision effect, while the double-pulse effectiveness curve consistent with the properties of transynaptic collision was apparent for a single pair of sites; the remaining 93% were associated with relatively flat effectiveness curves. While electrode misalignment could be responsible for these results, there was adequate sampling to suggest that the preponderance of first stage signals that give rise to the rewarding effects mediated by the lateral preoptic and ventral tegmental areas do not travel along the same fiber bundle. However, stimulation applied to both sites concurrently produces a summation that is roughly 40% greater than stimulation at either site alone, suggesting reasonable integration of the reward signals generated by lateral preoptic and ventral tegmental area stimulation.

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Cholecystokinin (CCK) is a peptide hormone which controls a number of important functions during the process of digestion. It is present in the gut and the central nervous system, although its exact role in the latter is not yet clear. Our interest was in the effects of intraperitoneal and intracerebral injections of CCK on brain stimulation reward and stimulation-induced feeding. Period thresholds for rewarding stimulation were unaffected by either route of peptide administration, whereas stimulation-induced feeding thresholds were weakly increased by centrally injected CCK. In addition, we evaluated stimulation-induced feeding using a more resolved measure and found it to provide clearer results. By actually measuring the amount of food eaten during a stimulation-induced feeding session, and not only the occurrence of feeding, CCK was shown to systematically decrease the total intake as a function of dose in an inverse manner. The efficiency of food utilization was calculated for each animal during the different phases of the experiment in order to monitor the effects of CCK on the animals' overall health. Centrally administered CCK appeared to increase the animals' efficiency and, furthermore, this level was sustained for the entire post-injection phase, about 2 weeks, suggesting a relatively enduring increase in metabolic rate. While the functional role of central CCK and other gastric peptides requires clarification, analyses which exploit the stimulation-induced feeding paradigm need to make use of more clearly defined microstructural variables.

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In recent years, we have been pursuing our mapping investigations of the substrate for brain-stimulation reward in regions of the anterior hypothalamic and lateral preoptic areas. However, one problem is that stimulation of these sites often generates overt seizures so that their suppression via a pharmacological means would be very useful. The sedative-hypnotic benzodiazepine, brotizolam, is reportedly a long-lasting anticonvulsant. Hence, its effects on motor seizures elicited from stimulation of the lateral preoptic area were evaluated in the first experiment. Both tested doses (5.0 and 7.5 mg/kg) of the drug were shown to significantly decrease the number, and marginally, the severity of stimulation-induced seizures; furthermore, this effect was relatively long lasting, up to about 3 h. The higher dose of brotizolam did not alter the single-pulse thresholds for self-stimulation, a requirement for evaluations of poststimulation excitability, the purpose of the second experiment. Here, our interest was in documenting whether the membrane properties of the stimulated neurons, as assessed by refractory periods, were altered by brotizolam. No differences in the time course of recovery were observed; refractoriness began between 0.4 and 0.8 ms, and reached 50% recovery by 2.0 ms, which is consistent with the pattern of poststimulation excitability typically measured at these sites. Thus, in addition to its long-lasting suppression of motor seizures in rats, brotizolam does not alter the time course of recovery from refractoriness of the neurons that mediate brain-stimulation reward in the lateral preoptic area.

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The self-stimulation paradigm was used to evaluate threshold changes following acute and chronic administration of the selective serotonergic reuptake inhibitor paroxetine; stimulation sites were located in medial forebrain bundle structures. Rats received daily systemic injections of one of three doses of paroxetine (2.5, 5, or 7.5 mg/kg), either with or without stimulation, while the last group received the same number of vehicle injections with stimulation. Frequency thresholds were collected over a period of 6 h on day 1 (acute phase); no marked difference in the values were observed over this time span. Thereafter, the animals were tested every third day (chronic phase), for a total of 11 sessions or roughly 31 days. Commencing around day 10 of the drug treatment, the higher dose of paroxetine produced a significant and persistent facilitation in self-stimulation thresholds, mimicking the delay in clinical response in humans that is well documented. We also monitored on a daily basis the animals' weights and food intake. A large difference in the percent efficiency of food utilization, measured by calculating the ratio of weight change to food intake, was observed between the animals receiving stimulation and those that were not, exclusive to the higher dose of paroxetine. The percent efficiency of food utilization remained low in the animals only receiving the drug treatment, whereas they returned to baseline levels and above in subjects receiving both paroxetine and stimulation. Two findings emerge from these data: 1) the paradigm appears to model the human response to this class of antidepressants, and 2) rewarding stimulation seems to counteract the drug-induced weight loss.

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Glycogen phosphorylase is the enzyme that regulates glycogenolysis and it appears that there is a relationship between central levels of glycogen and neuronal activity, which is influenced by a variety of neurotransmitters. In the present study, glycogen phosphorylase histochemistry was used to correlate changes in metabolic activity in response to rewarding lateral hypothalamic stimulation. Rats were allowed to self-stimulate for 1 h per day for ten consecutive days following which postmortem phosphorylase a activity was examined. Significant differences in optical density between the stimulated and contralateral hemispheres were found in three of the eight analyzed structures, two of which, the diagonal band of Broca and the caudate nucleus, showed a greater density of glycogen phosphorylase a on the stimulated side and the third, the habenula, had greater contralateral activity. In conclusion, our data suggest that glycogen phosphorylase activity is a viable but not weighty marker of energy alterations induced by chronic exposure to intracranial self-stimulation, and that it is generally consistent with the patterns revealed by other metabolic indices such as cytochrome oxidase and 2-deoxyglucose autoradiography.

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Bombesin's purported role in satiety mechanisms prompted this investigation of its effects on thresholds for stimulation-induced feeding and self-stimulation in the rat. Single electrodes were implanted in the lateral hypothalamus and the ability of each electrode to support self-stimulation and stimulation-induced feeding was evaluated at four current levels between 80 and 320 microA. The frequency thresholds associated with each current value were assessed following four intraperitoneal doses of bombesin, 2, 4, 8, and 16 micrograms/kg, as well as a saline dose. Bombesin increased the thresholds for stimulation-induced feeding at doses known to reduce food intake without influencing self-stimulation thresholds. From these findings we conclude that (1) the effects of peripheral bombesin on stimulation-induced feeding are analogous to its effects on normal feeding and (2) the data provide additional evidence for a pharmacological dissociation between stimulation-induced feeding and reward.

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Methodology used to support changes to the Regulations for bottled water in the Food and Drugs Act of Canada, which include criteria for Pseudomonas aeruginosa (0 colony-forming units/100 mL of water), was used to assess the survival of P. aeruginosa in inoculated bottled water. The effects of P. aeruginosa on the survival of Salmonella spp. in bottled water were also investigated. The methodology used in the isolation included the use of hydrophobic grid membrane filters, a resuscitation step on tryptic soy agar, and selective plating on P. aeruginosa selective agar for P. aeruginosa and on xylose lysine desoxycholate agar for salmonellae. Pseudomonas aeruginosa and salmonellae proliferated and survived in inoculated water for up to 100 days or longer. Pseudomonas aeruginosa had a synergistic effect on the survival of salmonellae, enabling them to survive for more than 140 days in double distilled water.

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Seventeen Canadian Federal, Provincial and Public Health Laboratories took part in different phases of a comparative/collaborative study that evaluated rapid methods to the standard Health Protection Branch (HPB) method for the detection of Salmonella. A variety of commercial media were tested, including Brilliant Green Sulpha Agar, Bismuth Sulphite Agar, Hektoen Enteric Agar, Xylose Lysine Deoxycholate Agar, EF-18 Agar and Rambach Agar. Each laboratory compared up to six of these different plating media. Plating of 123 salmonellae cultures and 28 artificially-inoculated foods showed the recovery of Salmonella spp. on the six plating media to be within one log. Therefore, quantitative testing of the media showed them to be comparable in the recovery of salmonellae. Qualitative testing of the six media during the comparative/collaborative study of various methods showed that EF-18 Agar recovered the greatest number of isolates. Hektoen Enteric Agar ranked second, with the other agars being comparable in their recovery of Salmonella spp. Problems with the various media are summarized. Based on our results and those of other researchers, it is recommended that Bismuth Sulphite Agar be compulsory and that at least one other agar be used for newly developed cultural procedures.

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