Weight Pulling: A Novel Mouse Model of Human Progressive Resistance Exercise.

This study describes a mouse model of progressive resistance exercise that utilizes a full-body/multi-joint exercise (weight pulling) along with a training protocol that mimics a traditional human paradigm (three training sessions per week, ~8-12 repetitions per set, 2 min of rest between sets, approximately two maximal-intensity sets per session, last set taken to failure, and a progressive increase in loading that is based on the individual's performance). We demonstrate that weight pulling can induce an increase in the mass of numerous muscles throughout the body. The relative increase in muscle mass is similar to what has been observed in human studies, and is associated with the same type of long-term adaptations that occur in humans (e.g., fiber hypertrophy, myonuclear accretion, and, in some instances, a fast-to-slow transition in Type II fiber composition). Moreover, we demonstrate that weight pulling can induce the same type of acute responses that are thought to drive these long-term adaptations (e.g., the activation of signaling through mTORC1 and the induction of protein synthesis at 1 h post-exercise). Collectively, the results of this study indicate that weight pulling can serve as a highly translatable mouse model of progressive resistance exercise.

Sleep deprivation in pigeons and rats using motion detection.

STUDY OBJECTIVES: Forced sleep deprivation results in substantial behavioral and physiologic effects in mammals. The disk-over-water (DOW) method produces a syndrome characterized by increased energy expenditure and a robust preferentially rapid-eye-movement sleep rebound upon recovery or eventual death after several weeks of sleep deprivation. The DOW has been used successfully only in rats. This paper presents a method to enforce long-term controlled sleep deprivation across species and to compare its effects in rats and pigeons. DESIGN AND INTERVENTION: A conveyor was substituted for the DOW disk. Behavior rather than electroencephalography was used to trigger arousal stimuli, as in gentle-handling deprivation. Rats and pigeons were deprived using this apparatus, and the results were compared with each other and with published reports. MEASUREMENTS AND RESULTS: The physiologic consequences and recovery sleep in rats were like those published for DOW rats. Magnitude of sleep loss and recovery patterns in pigeons were similar to those seen in rats, but expected symptoms of the sleep deprivation syndrome were absent in pigeons. The use of a motion trigger allowed us to measure and, thus, to assess the quality and impact of the procedure. CONCLUSION: Prolonged and controlled sleep deprivation can be enforced using automated motion detection and a conveyor-over-water system. Pigeons and rats, deprived of sleep to the same extent, showed similar patterns of recovery sleep, but pigeons did not exhibit the hyperphagia, weight loss, and debilitation seen in rats.

Sleep deprivation in the pigeon using the Disk-Over-Water method.

A well-defined sleep deprivation (SD) syndrome has been observed in studies with rats under conditions of severe sleep loss on the Disk-Over-Water (DOW) apparatus. Observation of the sleep deprivation syndrome across taxa would assist in the elucidation of the function of sleep. In the present study, the effects of total sleep deprivation were assessed in pigeons, a biologically relevant choice given that birds are the only non-mammalian taxon known to exhibit unequivocal rapid-eye-movement (REM) sleep and non-REM (NREM) sleep. Pigeons were deprived of sleep for 24-29 days on the DOW by rotating the disk and requiring them to walk whenever sleep was initiated. Control (C) birds were also housed on the DOW and required to walk only when the deprived (D) birds were required to walk due to sleep initiation. NREM and REM sleep amounts were reduced from baseline during the deprivation for both D and C birds, although D birds obtained less NREM sleep than controls. Across the deprivation, D birds had their total sleep reduced by 54% of baseline (scored in 4 s epochs), whereas previous studies in rats on the DOW reported total sleep reduction of as much as 91% (scored in 30 s epochs). Pigeons proved to be more resistant to sleep deprivation by the DOW method and were much more difficult to deprive over the course of the experiment. Overall, the pigeons showed recovery sleep patterns similar to those seen in rats; i.e., rebound sleep during recovery was disproportionately composed of REM sleep. They did not, however, show the obvious external physical signs of the SD syndrome nor the large metabolic and thermoregulatory changes associated with the syndrome. The DOW method was thus effective in producing sleep loss in the pigeon, but was not as effective as it is in rats. The absence of the full SD syndrome is discussed in the context of limitations of the DOW apparatus and the possibility of species-specific adaptations that birds may possess to withstand or adapt to conditions of limited sleep opportunity.

Stimulation of lateral septum CRF2 receptors promotes anorexia and stress-like behaviors: functional homology to CRF1 receptors in basolateral amygdala.

The corticotropin-releasing factor (CRF) system is the primary central mediator of stress-like states, coordinating behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well documented effect of CRF receptor agonist administration, the central sites and behavioral processes underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating decreases in feeding produced by the CRF1/CRF2 receptor agonist urocortin. Separate groups of food-restricted male Sprague Dawley rats were given infusions of urocortin (0, 50, 125, 250 ng/0.5 microl) into the lateral septum (LS) and immediately afterward were rated on a wide array of behaviors (locomotion, rearing, grooming, stereotypies) including a microstructural analysis of ingestive behavior. Intra-LS urocortin infusion dose-dependently reduced feeding and drinking while concomitantly increasing grooming, stereotypies, and ethological plus traditional measures of anxiety-like responses in the elevated plus-maze. Urocortin infusion into neighboring sites (lateral ventricle, medial caudate) had no effects. Coinfusion into the LS of the mixed CRF1/CRF2 receptor antagonist D-Phe-CRF(12-41) (0, 100, 1000 ng/0.5 microl) or the novel selective CRF2 receptor antagonist Astressin2B (0, 500, 1000 ng/0.5 microl) blocked urocortin-induced effects, but the CRF1-selective antagonist NBI27914 (0, 500, 1000 ng/0.5 microl) had no effect, although it completely reversed the behavioral sequelae of CRF when infused into the basolateral amygdala. These results indicate that one of the modes through which the CRF system promotes anorexia is the recruitment of stress-like states after stimulation of CRF2 receptors within the LS.

Predator threat induces behavioral inhibition, pituitary-adrenal activation and changes in amygdala CRF-binding protein gene expression.

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, extreme BI is associated with anxiety-related psychopathology. When rats are exposed to a natural predator they display stress- and anxiety-related behavioral alterations and physiological activation. To develop a preclinical rodent model to study mechanisms underlying human BI and anxiety, we examined the extent to which ferret exposure elicits anxiety-related BI and HPA and amygdala activation of the CRF system. In the first experiment, BI and other behaviors were assessed in the presence or absence of a ferret. In the second experiment, ferret-induced corticosterone release and changes in brain c-fos expression were assessed. In the final experiment, gene chip and quantitative real time-PCR analyses were performed on amygdala tissue from control and ferret-exposed rats. Ferret exposure increased BI and submissive posturing, as well as plasma corticosterone and the number of Fos-positive cells in several brain regions including the amygdala. Gene expression analysis revealed increased amygdalar mRNA for CRF-binding protein, but not the CRF1 receptor, CRF2 receptor or CRF. In rodents, ferret exposure can be used to elicit anxiety-related BI, which is associated with HPA and amygdala activation. Since the amygdala and the CRF system have been implicated in adaptive and maladaptive anxiety responses in humans, these data support use of our rodent model to further investigate mechanisms underlying anxiety-related psychopathology in humans.

Corticotropin-releasing factor-1 receptors in the basolateral amygdala mediate stress-induced anorexia.

Corticotropin-releasing factor (CRF) receptor activation within the basolateral amygdala (BLA) has been relatively unexplored compared with the central nucleus of the amygdala (CeA), despite the fact that CRF receptors are more densely distributed in BLA than in CeA. The authors show that infusion of CRF into BLA, but not CeA, decreases feeding and increases grooming. These effects are mediated by CRF-sub-1 receptors, because they are blocked by intra-BLA treatment with NBI27914 (NBI), a CRF-sub-1 antagonist, but not Astressin 2B, a CRF-sub-2 antagonist. Exposure to a stressor results in behaviors identical to those seen after intra-BLA CRF infusion. These stress-induced changes are prevented by pre-stress treatment with NBI but not Astressin 2B. These data demonstrate that stimulation of intra-BLA CRF-sub-1 receptors is both necessary and sufficient for eliciting stress-induced anorexia and grooming.

Corticotropin-releasing factor inhibits maternal aggression in mice.

Lactating females that fiercely protect offspring exhibit decreased fear and anxiety. The authors tested whether decreased corticotropin-releasing factor (CRF), an activator of fear and anxiety, plays a functional role in maternal aggression. Intracerebroventricular (icv) injections of CRF (1.0 and 0.2 microg, but not 0.02 microg) significantly inhibited maternal aggression but not other maternal behaviors. The CRF antagonist D-Phe-CRF(12-41) had no effect. Maternal aggression and icv CRF (0.2 microg) induced Fos in 11 of the same regions, including the lateral and medial septum, the bed nucleus of the stria terminalis, the medial and central amygdala, the periaqueductal gray, the dorsal raphe, and the locus coeruleus. These findings suggest that decreased CRF is necessary for maternal aggression and may act by altering brain activity in response to an intruder.

Reduction of stress-induced behavior by antagonism of corticotropin-releasing hormone 2 (CRH2) receptors in lateral septum or CRH1 receptors in amygdala.

Although corticotropin-releasing hormone (CRH), a regulator of stress responses, acts through two receptors (CRH1 and CRH2), the role of CRH2 in stress responses remains unclear. Knock-out mice without the CRH2 gene exhibit increased stress-like behaviors. This profile could result either directly from the absence of CRH2 receptors or indirectly from developmental adaptations. In the present study, CRH2 receptors were acutely blocked by alpha-helical CRH (alpha(h)CRH, CRH1/CRH2 antagonist; 0, 30, 100, and 300 ng) infusion into the lateral septum (LS), which abundantly expresses CRH2 but not CRH1 receptors. Freezing, locomotor activity, and analgesia were tested after infusion. Intra-LS alpha(h)CRH blocked shock-induced freezing without affecting activity or pain responses; infusions into lateral ventricle or nucleus of the diagonal band had no effects. The same behavioral profile was obtained with d-Phe-CRH((12-41)) (100 ng), another CRH1/CRH2 antagonist. A selective CRH1 antagonist (NBI27914), in doses that reduced freezing on intra-amygdala (central nucleus) infusion (0, 0.2, and 1.0 microg), did not affect freezing when infused into the LS. Ex vivo autoradiography revealed that binding of [125I]sauvagine, a mixed CRH1/CRH2 agonist, was prevented in the LS by previous intra-LS infusion of alpha(h)CRH but not NBI27914. In vitro studies demonstrated that [125I]sauvagine binding in the LS could be inhibited by a CRH1/CRH2 antagonist but not by the selective CRH1 receptor antagonist, confirming that in the LS, alpha(h)CRH antagonized exclusively CRH2 receptors. Acute antagonism of CRH2 receptors in the LS thus produces a behaviorally, anatomically, and pharmacologically specific reduction in stress-induced behavior, in contrast to results of recent knock-out studies, which induced congenital and permanent CRH2 removal. CRH2 receptors may thus represent a potential target for the development of novel CRH system anxiolytics.