Changes in Brain-Derived Neurotrophic Factor Expression Influence Sleep-Wake Activity and Homeostatic Regulation of Rapid Eye Movement Sleep.

STUDY OBJECTIVES: Brain-derived neurotrophic factor (BDNF) expression and homeostatic regulation of rapid eye movement (REM) sleep are critical for neurogenesis and behavioral plasticity. Accumulating clinical and experimental evidence suggests that decreased BDNF expression is causally linked with the development of REM sleep-associated neuropsychiatric disorders. Therefore, we hypothesize that BDNF plays a role in sleep-wake (S-W) activity and homeostatic regulation of REM sleep. METHODS: Male and female wild-type (WT; BDNF +/+) and heterozygous BDNF (KD; BDNF +/-) rats were chronically implanted with S-W recording electrodes to quantify baseline S-W activity and REM sleep homeostatic regulatory processes during the light phase. RESULTS: Molecular analyses revealed that KD BDNF rats had a 50% decrease in BDNF protein levels. During baseline S-W activity, KD rats exhibited fewer REM sleep episodes that were shorter in duration and took longer to initiate. Also, the baseline S-W activity did not reveal any sex difference. During the 3-hour selective REM sleep deprivation, KD rats failed to exhibit a homeostatic drive for REM sleep and did not exhibit rebound REM sleep during the recovery S-W period. CONCLUSION: Interestingly, both genotypes did not reveal any sex difference in the quality and/or quantity of REM sleep. Collectively, these results, for the first time, unequivocally demonstrate that an intact BDNF system in both sexes is a critical modulator for baseline and homeostatic regulation of REM sleep. This study further suggests that heterozygous BDNF knockdown rats are a useful animal model for the study of the cellular and molecular mechanisms of sleep regulation and cognitive functions of sleep.

Dominance status alters restraint-induced neural activity in brain regions controlling stress vulnerability.

Understanding the cellular mechanisms that control resistance and vulnerability to stress is an important step toward identifying novel targets for the prevention and treatment of stress-related mental illness. In Syrian hamsters, dominant and subordinate animals exhibit different behavioral and physiological responses to social defeat stress, with dominants showing stress resistance and subordinates showing stress vulnerability. We previously found that dominant and subordinate hamsters show different levels of defeat-induced neural activity in brain regions that modulate coping with stress, although the extent to which status-dependent differences in stress vulnerability generalize to non-social stressors is unknown. In this study, dominant, subordinate, and control male Syrian hamsters were exposed to acute physical restraint for 30min and restraint-induced c-Fos immunoreactivity was quantified in select brain regions. Subordinate animals showed less restraint-induced c-Fos immunoreactivity in the infralimbic (IL), prelimbic (PL), and ventral medial amygdala (vMeA) compared to dominants, which is consistent with the status-dependent effects of social defeat stress. Subordinate animals did not show increased c-Fos immunoreactivity in the rostroventral dorsal raphe nucleus (rvDRN), which is in contrast to the effects of social defeat stress. These findings indicate that status-dependent changes in neural activity generalize from one stressor to another in a brain region-dependent manner. These findings further suggest that while some neural circuits may support a generalized form of stress resistance, others may provide resistance to specific stressors.

Beyond Emotional and Spatial Processes: Cognitive Dysfunction in a Depressive Phenotype Produced by Long Photoperiod Exposure.

Cognitive dysfunction in depression has recently been given more attention and legitimacy as a core symptom of the disorder. However, animal investigations of depression-related cognitive deficits have generally focused on emotional or spatial memory processing. Additionally, the relationship between the cognitive and affective disturbances that are present in depression remains obscure. Interestingly, sleep disruption is one aspect of depression that can be related both to cognition and affect, and may serve as a link between the two. Previous studies have correlated sleep disruption with negative mood and impaired cognition. The present study investigated whether a long photoperiod-induced depressive phenotype showed cognitive deficits, as measured by novel object recognition, and displayed a cognitive vulnerability to an acute period of total sleep deprivation. Adult male Wistar rats were subjected to a long photoperiod (21L:3D) or a normal photoperiod (12L:12D) condition. Our results indicate that our long photoperiod exposed animals showed behaviors in the forced swim test consistent with a depressive phenotype, and showed significant deficits in novel object recognition. Three hours of total sleep deprivation, however, did not significantly change novel object recognition in either group, but the trends suggest that the long photoperiod and normal photoperiod groups had different cognitive responses to total sleep deprivation. Collectively, these results underline the extent of cognitive dysfunction present in depression, and suggest that altered sleep plays a role in generating both the affective and cognitive symptoms of depression.

Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep.

Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA-12). On experimental days, rats received PPT microinjections and their sleep-wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA-12 dose-dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose-dependent suppression of PPT BDNF up-regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF-TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive.

Winning agonistic encounters increases testosterone and androgen receptor expression in Syrian hamsters.

Winning aggressive disputes is one of several experiences that can alter responses to future stressful events. We have previously tested dominant and subordinate male Syrian hamsters in a conditioned defeat model and found that dominant individuals show less change in behavior following social defeat stress compared to subordinates and controls, indicating a reduced conditioned defeat response. Resistance to the effects of social defeat in dominants is experience-dependent and requires the maintenance of dominance relationships for 14days. For this study we investigated whether winning aggressive interactions increases plasma testosterone and whether repeatedly winning increases androgen receptor expression. First, male hamsters were paired in daily 10-min aggressive encounters and blood samples were collected immediately before and 15min and 30min after the formation of dominance relationships. Dominants showed an increase in plasma testosterone at 15min post-interaction compared to their pre-interaction baseline, whereas subordinates and controls showed no change in plasma testosterone. Secondly, we investigated whether 14days of dominant social status increased androgen or estrogen alpha-receptor immunoreactivity in brain regions that regulate the conditioned defeat response. Dominants showed more androgen, but not estrogen alpha, receptor immuno-positive cells in the dorsal medial amygdala (dMeA) and ventral lateral septum (vLS) compared to subordinates and controls. Finally, we showed that one day of dominant social status was insufficient to increase androgen receptor immunoreactivity compared to subordinates. These results suggest that elevated testosterone signaling at androgen receptors in the dMeA and vLS might contribute to the reduced conditioned defeat response exhibited by dominant hamsters.