Neonatal Hypoxic-Ischemic Brain Injury Leads to Sex-Specific Deficits in Rearing and Climbing in Adult Mice

The study examined the morphological and long-term behavioral impacts of neonatal hypoxic-ischemic brain injury in a mouse model. We investigated the modification of different behavioral domains, such as spontaneous climbing, which represents fine motor skills. We also focused on sex-dependent differences during hypoxic-ischemic encephalopathy. The Rice-Vannucci model of hypoxia-ischemia was used, adjusted and adapted to 7-day-old C57BL/6NTac mice. The effects of induced hypoxia and ischemia were also studied separately. At postnatal day 60, mice underwent behavioral testing using the LABORAS apparatus. The perfusion for histological evaluation was performed one day after the behavioral analyses. In groups with separately induced hypoxia or ischemia, the observed alterations in behavior were not accompanied by morphological changes in the cortex or hippocampal formation. Female mice naturally climbed significantly more and hypoxic females reared less than hypoxic males (p<0.05). Male mice postnatally exposed to hypoxia-ischemia exhibited significantly lower vertical activity and higher horizontal activity (p<0.05). Mild hypoxic damage may not be morphologically detectable but may induce substantial behavioral changes in adult mice. There were significant differences between horizontal and vertical activity in reaction to hypoxia-ischemia. Our study indicates that the importance of behavioral testing is irreplaceable and may be reflected in neonatal medicine.

Influence of ketotifen and conventional antiepileptic drugs on the exploratory and spontaneous locomotor activity in mice

Drug interactions are major problems in polytherapy, especially in epilepsy, and inappropriate drug selection may result in increased frequency of seizures. In this study, the influence of histamine type 1 (H1) receptor antagonist ketotifen and four chosen antiepileptic drugs (AEDs) on mice activity was examined. We evaluated three parameters of locomotor activity in mice: horizontal total activity with total distance and vertical activity, as well as animal spontaneous activity. Experiments were divided into two 15-minutes studies. During the first 15 minutes, we examined exploratory activity in mice; in the second period, spontaneous activity was tested. In the experiment, Ketotifen or vehicle were administered once or for 7 days daily, whereas AEDs were given only once before test performance. Our results show that ketotifen given alone once or for 7 days significantly increased exploratory locomotor activity in mice without affecting their spontaneous activity. However, in combination with AEDs, ketotifen given once or for 7 days differently affected spontaneous and locomotor activity in mice. Our study indicates that the combination of ketotifen with AEDs needs special attention in pharmacotherapy of epilepsy.

Seasonal depth and temperature use, and diel movements of lake trout (Salvelinus namaycush) in a subarctic lake

We conducted a multi-year acoustic telemetry study of lake trout (Salvelinus namaycush (Walbaum, 1792)) in a small subarctic lake to investigate depth and temperature occupancy, and vertical activity across seasons (summer, fall, and winter), diel periods (day, twilight, and night), and during summer periods of 24 h light (day and twilight). Analyses using generalized additive mixed models revealed a high degree of individual variation in depth occupancy independent of the factors hour of day, season, and diel period, whereas temperature occupancy and vertical activity were explained using the three combined factors. Habitats occupied were typically 9–20 m and 6–9.5 °C in summer, 1–3 m and 2–15 °C in fall during presumed spawning, and ≤6 m and <3 °C in winter. Lake trout exhibited partial diel migration where individuals displayed a variety of vertical migratory directions within and among seasons or diel period, including during periods of 24 h light. Fish were most vertically active during periods of daylight and in fall. During 24 h light, some lake trout performed crepuscular movements, whereas individual behaviour best explained modelled depth and temperature occupancy and vertical activity. The variety of vertical patterns among individuals and seasons suggests multifactor proximate causes of partial diel migration and crepuscular movements.

Effect of famotidine in combination with antiepileptic drugs on locomotor activity in mice

Histamine type 2 receptor antagonists are one of the most commonly used agents to treat peptic ulcer disease. Since patients with epilepsy may have many comorbidities, the aim of this study was to investigate the influence of one of the strongest second generation histamine type 2 receptor antagonist, famotidine, on the exploratory and spontaneous activity in mice after 1 or 7 days treatment. Additionally, the interaction between famotidine and antiepileptics: carbamazepine, phenytoin, phenobarbital or valproate and their effect on animals activity was also evaluated. Locomotor activity was monitored electronically using a Digiscan analyzer in relation to ambulatory and rearing activities, as well as total distance travelled by animals during 15 minute periods. Results of our study indicate that famotidine administered alone did not modulate three variables of exploratory motor activity (horizontal activity, total distance and vertical activity) in mice. On the other hand, famotidine co-administered with valproate (1 day) or phenobarbital (1 day or 7 days) worsened vertical activity in mice in exploratory time. Similarly, impairment in horizontal activity in mice was observed when famotidine was given with phenobarbital (1 or 7 days). An increase in total distance in mice after famotidine alone or in combination with tested antiepileptic drugs was also shown. Moreover, famotidine alone or together with antiepileptic agents significantly impaired spontaneous locomotor activity in mice. The presented results show that famotidine administration to patients with epilepsy should be considered as potentially hazardous.

GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy

Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.

Diel vertical migration of adult burbot: a dynamic trade-off among feeding opportunity, predation avoidance, and bioenergetic gain

Diel vertical migration (DVM) of pelagic organisms is typically attributed to bioenergetic gain, foraging opportunity, predator avoidance, and multifactor hypotheses. While a number of benthic species perform nightly migrations into shallower waters, the function of these DVMs has largely been ignored in benthic fishes. We used depth and temperature sensing telemetry to investigate DVM function in burbot (Lota lota), a freshwater benthic piscivore. We modeled the influence of season, diel period, and body size on the depth, vertical activity, migration probability, and thermal experience of 47 adult burbot over 2 years in a reservoir in British Columbia, Canada. Burbot were found to occupy significantly shallower water at night than during the day. Our results, which showed elevated nightly activity and a seasonal size-structured depth distribution during DVMs, suggest these migrations likely provide a feeding opportunity “window” for this nocturnal predator, constrained by predation or cannibalism threats to smaller individuals. The observed thermal experience patterns suggest DVM may also provide a seasonal bioenergetic advantage. Our detection of within-individual plasticity in migration strategy is indicative of a partial migration. Taken together, our results suggest a multifactor DVM hypothesis: a dynamic trade-off among bioenergetic advantage, foraging opportunity, and predation threat.