Ross P. Henderson

AKT Signaling within the Ventral Tegmental Area Regulates Cellular and Behavioral Responses to Stressful Stimuli

BACKGROUND The neurobiological mechanisms by which only a minority of stress-exposed individuals develop psychiatric diseases remain largely unknown. Recent evidence suggests that dopaminergic neurons of the ventral tegmental area (VTA) play a key role in the manifestation of stress vulnerability. METHODS Using a social defeat paradigm, we segregated susceptible mice (socially avoidant) from unsusceptible mice (socially interactive) and examined VTA punches for changes in neurotrophic signaling. Employing a series of viral vectors, we sought to causally implicate these neurotrophic changes in the development of avoidance behavior. RESULTS Susceptibility to social defeat was associated with a significant reduction in levels of active/phosphorylated AKT (thymoma viral proto-oncogene) within the VTA, whereas chronic antidepressant treatment (in mice and humans) increased active AKT levels. This defeat-induced reduction in AKT activation in susceptible mice was both necessary and sufficient to recapitulate depressive behaviors associated with susceptibility. Pharmacologic reductions in AKT activity also significantly raised the firing frequency of VTA dopamine neurons, an important electrophysiologic hallmark of the susceptible phenotype. CONCLUSIONS These studies highlight a crucial role for decreases in VTA AKT signaling as a key mediator of the maladaptive cellular and behavioral response to chronic stress.

Daily cycles in body temperature, metabolic rate, and substrate utilization in pigeons: influence of amount and timing of food consumption

Pigeons lived in individual chambers where instantaneous metabolic rate (MR; indirect calorimetry), body temperature (Tb), and substrate utilization (RQ) were measured 24 times each hour throughout the 12h:12h light:dark cycle. The amount of food consumed influenced the amplitude of the MR and Tb cycles, primarily by affecting the dark-phase segment of the cycle: when food was consumed ad lib, low-amplitude daily cycles in MR and Tb occurred in which levels in the dark phase were lower than in the light; during reduced food intake in restricted feeding or in fasting, high-amplitude cycles occurred primarily because nocturnal hypometabolism and hypothermia developed; in restricted feeding, the level of MR and Tb during the dark-phase segment of the cycle was directly related to short-term variation in amount consumed. The timing of food consumption primarily affected the light-phase segment of the MR and Tb cycles: when feeding was restricted to a time late in the light phase, these measures became depressed early in the light phase, and then greatly elevated near the scheduled time of feeding. This distinctive light-phase pattern developed quickly after the restricted feeding schedule began and may reflect the influence of a circadian food-entrainable oscillator. RQ indicated carbohydrate utilization for most of the 24-h cycle during ad lib feeding and in restricted feeding. However, approximately 2 h before the first feeding bout of the day, the RQ cycle indicated a sizable shift towards lipid utilization, which terminated after the bout was completed. There was a smaller, more transient, decrease in RQ near the time of the light-dark transition, which may imply cessation of digestive activity in preparation for the nocturnal decrease in Tb. During fasting, RQ indicated lipid utilization throughout the entire cycle. Whole-day energy expenditure by pigeons in these laboratory circumstances was shown to be closely related to the changes in within-day cycles associated with variations in the amount and timing of food intake.

High dietary NaCl early in development enhances mean arterial pressure of adult rats

We investigated the long-term influence of early dietary NaCl on adult mean arterial pressure (MAP) and heart rate (HR), assessed continuously for 7 weeks when fed water and chow containing 1% NaCl (weeks 1, 4, 7), 0% NaCl (weeks 2-3), and 3% NaCl (weeks 5-6) while on a 12:12 light/dark cycle. Subjects were offspring of female Sprague-Dawley rats fed solid chow consisting of either 0.1% (basal), 1% (intermediate), or 3% (high) NaCl throughout pregnancy and lactation. After weaning on postnatal day (PD) 21, offspring were fed the same NaCl diet of their mother until PD 30, at which time all offspring were given Purina 5001 diet (1% NaCl) as their solid chow. On PD 60, 22 adult male offspring (eight basals, six intermediates, eight highs) were implanted with an aortic electronic sensor for transmitting blood-pressure signals by telemetry. MAP and HR varied significantly across the 7-week testing period in association with dietary NaCl levels. The three perinatal salt groups had similar HR levels on normal 1% NaCl chow. However, HR increased in all groups during 0% NaCl and decreased in all groups during 3% NaCl. In contrast, the average MAP levels were significantly greater in the highs compared to both the intermediate and basal groups during both dark and light periods. MAP increased in high and basal groups during both 0% and 3%; however, the increase was more pronounced in the highs. In conclusion, exposure to high levels of dietary NaCl early in development led to a persistent increase in MAP in adulthood.

Diet-induced obesity and cardiovascular regulation in C57BL/6J mice.

1. In the present study, we determined the effect of diet‐induced obesity on cardiovascular and metabolic regulation in mice at standard laboratory temperatures (ambient temperature (Ta) = 22°C) and during exposure to thermoneutrality (Ta = 30°C).

Vigilance states and body temperature during the circadian cycle in fed and fasted pigeons (Columba livia)

Fasting induces nocturnal hypothermia in pigeons. Slow-wave sleep (SWS) and paradoxical sleep (PS) are associated with reduced heat production in pigeons. The possibility that fasting-induced nocturnal hypothermia is related to increased SWS and PS was examined by comparing body temperature (Tb) and vigilance states when pigeons were fed and fasted. The results showed that when Tb is decreasing near the beginning of the dark phase, the percentage of total recording time (%TRT) spent in SWS and PS was elevated in fasting due to increased frequency of episodes and increased duration of PS episodes. When Tb was low during the middle segment of the dark phase, SWS was elevated in fasting due to increased episode duration. However, fasting did not alter PS, which increased in %TRT across the segment due to increased episode frequency. When Tb was rising during the final hours of dark, SWS remained elevated in fasting and %TRT in SWS and PS was relatively high. SWS and PS may promote the fasting pigeons entry into, and maintenance of, nocturnal hypothermia.Fasting induces nocturnal hypothermia in pigeons. Slow-wave sleep (SWS) and paradoxical sleep (PS) are associated with reduced heat production in pigeons. The possibility that fasting-induced nocturnal hypothermia is related to increased SWS and PS was examined by comparing body temperature (Tb) and vigilance states when pigeons were fed and fasted. The results showed that when Tb is decreasing near the beginning of the dark phase, the percentage of total recording time (%TRT) spent in SWS and PS was elevated in fasting due to increased frequency of episodes and increased duration of PS episodes. When Tb was low during the middle segment of the dark phase, SWS was elevated in fasting due to increased episode duration. However, fasting did not alter PS, which increased in %TRT across the segment due to increased episode frequency. When Tb was rising during the final hours of dark, SWS remained elevated in fasting and %TRT in SWS and PS was relatively high. SWS and PS may promote the fasting pigeons entry into, and maintenance of, nocturnal hypothermia.

Antidepressant treatment can normalize adult behavioral deficits induced by early-life exposure to methylphenidate.

BACKGROUND Methylphenidate (MPH) is prescribed for the treatment of attention-deficit/hyperactivity disorder. Exposure to MPH before adulthood causes behavioral deficits later in life, including anxiety- and depression-like behaviors and decreased responding to natural and drug rewards. We examined the ability of fluoxetine (FLX), a selective serotonin reuptake blocker, to normalize these MPH-induced behavioral deficits. METHODS Male rats received MPH (2.0 mg/kg) or saline (VEH) during preadolescence (postnatal day [PD] 20-35). When adults, rats were divided into groups receiving no treatment, acute or chronic FLX, and behavioral reactivity to several emotion-eliciting stimuli were assessed. RESULTS The MPH-treated rats were significantly less responsive to natural (i.e., sucrose) and drug (i.e., morphine) rewards and more sensitive to stress- and anxiety-eliciting situations. These MPH-induced deficits were reversed by exposure to FLX. CONCLUSIONS These results indicate that exposure to MPH during preadolescence leads to behavioral alterations that endure into adulthood and that these behavioral deficits can be normalized by antidepressant treatment. These results highlight the need for further research to better understand the effects of stimulants on the developing nervous system and the potential enduring effects resulting from early-life drug exposure.

A system for studying the microstructure of ingestive behavior in mice

A system for long-term monitoring of mouse eating and drinking behavior with 6-s resolution is described. The apparatus utilizes infrared beams to monitor activity at a single feeding port and electronic contact detector circuitry to record individual licks at two drinking ports. Eight SWR/J mice were monitored using this system and data from the last day of testing with food and water were analyzed. Mice ate an average of 4.54 +/- 0.40 g of powdered food and drank an average of 5.81 +/- 0.65 ml of water. Mice had an average of 36.25 +/- 3.96 food bouts and 32.25 +/- 7.56 water bouts lasting 3.00 +/- 0.48 and 0.88 +/- 0.35 min, respectively. Information regarding the temporal association between eating and drinking and the circadian patterns of ingestion was provided, utilizing customized software that augments the system. Important implications for the use of mice in ingestion pattern research are discussed.

Energetic responses of pigeons during food deprivation and restricted feeding

Pigeons ate food ad lib, then fasted for several days, and finally ate a controlled amount of food once a day for several months to maintain body weight at 80% of the ad lib value. Whole-body dry heat loss (HL) and core body temperature (Tb) were measured continuously for each pigeon. Thermal conductance (C) was calculated from HL and Tb. Relative to ad lib feeding, 24-h HL was reduced by approximately 50% during fasting and controlled feeding. The majority of energy savings was achieved by lowering C, which appeared to maintain a saturated low value throughout most of the light and dark phases. Therefore, the pigeons characteristic high Tb in the daily light phase during fasting and food restriction does not necessarily imply high energy expenditure. In the dark phase, the fasting pigeons characteristically low Tb enhances energy savings already being achieved through lowered C. The daily cycle in Tb, and to a lesser extent in HL and C, was strongly altered by occasional probe variations in the amount of food given at the single daily feeding and by a shift in the time of the daily feeding.

Magnetic Field Conditioned Taste Aversion In Rats

Conditioned taste aversion is a common classic conditioning procedure used to identify noxious stimuli. When a rat is given a taste solution, the conditioned stimulus (CS), followed by an unpleasant experience, the unconditioned stimulus (US), the rat will avoid consumption of the CS in future presentations. These experiments use the taste aversion procedure to examine the effect of exposure to a high magnetic field. A solution consisting of 3.0 g glucose and 1.25 g saccharin per 1 L of solution (G+S) was used as the CS and a 9.4-T magnet served as the US. In Experiment 1, all rats received a 10 min presentation of the G+S solution followed by either a 30 min exposure to the magnetic field (Magnet, n = 8), a 30-min exposure in a container with similar conditions but lacking the magnetic field (Sham, n = 8), or no exposure (Control, n = 8). The Magnet Group showed a taste aversion on the first day of preference testing (p < 0.05). Experiment 2 employed the same US-CS protocol for 3 consecutive days of conditioning. The Magnet Group demonstrated a taste aversion for the postexposure Days 1-8 (p < 0.01). There was no difference between the Sham and Control Groups in either experiment. The results of this study clearly demonstrate that the rats associated the G+S solution with the experience of being exposed to the high magnetic field and avoided the solution in subsequent presentations.

High Lick Rate Is Maintained Throughout Spontaneous Liquid Meals in Freely Feeding Rats

To investigate the microstructure of spontaneous meals in freely feeding rats, 16 adult male Sprague Dawley rats were housed individually in custom-designed lickometer cages and maintained on a milk diet. Licks were recorded over 23 h at millisecond accuracy via a computer-controlled lickometer. Analysis of lick data revealed an average of about 12 discrete meals/day occurring mainly during the dark phase. The most striking feature of both dark and light meals was the maintenance of a high initial rate of licking until an abrupt decline at the end of the meal. This pattern of licking is very different from the exponential decay of lick rate reported in scheduled test meals of palatable solutions. Thus, the microstructure of licking for meals is affected in an apparently fundamental way by whether a meal is scheduled or spontaneous, suggesting a basic difference in the underlying physiologic controls.