Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

Treatment of uterine fibroids with implants of gonadotropin-releasing hormone agonist: assessment by hysterography.

The effect of a potent, subcutaneously injected gonadotropin-releasing hormone (GnRH analog) (Buserelin, Hoechst, Frankfurt/Main West Germany) on the size of uterine leiomyomas and the uterine cavity area was studied in a group of 20 women. In all patients except 1, the uterine cavity area calculated by hysterosalpingography was decreased, with an average decrease of 35% (from 12.0 +/- 5.4 cm2 to 7.8 +/- 3.3 cm2) by 8 weeks of therapy. Significant decrease was observed in the group of women with initial uterine cavity area greater than 10 cm2. In patients with very large submucous fibroids, myomectomy by hysteroscopy and neodymium:YAG laser was easily performed. Rapid relief of symptoms such as menometrorrhagia permits the restoration of a normal hemoglobin concentration. In conclusion, use of GnRH analog represents an adjunct for preoperative reduction of tumor size and may permit surgical treatment by hysteroscopy

Cardiovascular and locomotory parameters during training in Thoroughbred racehorses: a multi-national study

Studies assessing concurrent speed, cardiovascular physiology and biomechanical parameters in racehorses during training have been rarely reported, mostly due to a lack of available comprehensive technology. Here, using a validated device (the ‘Equimetre’™) that records all parameters simultaneously, we report the effect of increased training speed and thus intensity, from slow canter to hard gallop, on racehorse heart rate, heart rate recovery and on biomechanical parameters, such as stride length and frequency. We also demonstrate the effects of varying track surface, horse age and sex. Cohorts comprised a total of 509 Thoroughbred racehorses in-training in either Australia or France, completing a total of 1,124 and 6,016 training sessions, respectively. Horses varied by age (2-9 years old) and sex (including geldings) and were trained by either a single trainer (Australia) or two trainers (France); both using multiple training centres that varied by track surface (sand, turf or fibre). Data were analysed using Analysis of Variation (ANOVA) or linear mixed-effect models as appropriate. Racehorses increased speed predominantly by an increment in stride length, then frequency, both of which varied according to track surface (shorter stride on sand; P<0.001). Cardiovascular parameters (peak, and recovery of, heart rate) increased with training intensity, but not linearly (Ptrend<0.001). Older horses recorded lower heart rate at 15 mins after training (P=0.002), often due to lower achieved peak heart rate at most training intensities (P<0.001 for the cohort in Australia). In conclusion, this immersive field study demonstrates the value of technology for recording physiological and biomechanical parameters of racehorses-in-training. The data could inform trainers, jockeys and owners on aspects of individual racehorse health, welfare and suitability for certain races

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states