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S. 16.03 BDNF, depression and sleep: perspectives from animal models
S136
S.16. Translational research on sleep and depression
S.16. Translational research on sleep and depression S.16.01 Is the vesicular glutamate transporter type 3 (VGLUT3) a novel marker linking mood to sleep? A study in VGLUT3 deficient mice V. Fabre1 ° , F. Henderson1 , V. Vialou1 , S. El Mestikawy1 Paris Seine NPS − Institut de Biologie Paris Seine IBPS − Sorbonne Universit´es, UPMC UM CR18 − INSERM U1130 − CNRS UMR 8246, Paris, France 1 Neuroscience
Impaired sleep is a symptom that often associates with affective disorders including depression and anxiety. However, the mechanisms underlying both mood and sleep regulation remain to be determined. Thus, sleep profiling in animal models of mood disorders is a critical step to further define the links between sleep and emotional behaviors. Here, we propose to assess sleep and wake regulation in mice lacking the Vesicular Glutamate Transporter Type 3 (VGLUT3). VGLUT3 accumulates glutamate into synaptic vesicles to promote its regulated release. Interestingly, VGLUT3 is present in subclasses of 5-HT neurons and terminals. Recent data have suggested that VGLUT3 positively modulates 5-HT raphe transmission as its absence reduces hippocampal extracellular 5-HT levels [1]. In addition, VGLUT3 deletion promotes a marked increase in anxiety behavior. As decreased serotonergic tone is tightly associated with sleep and mood disorders, we assessed sleep/wake patterns in VGLUT3 knock-out mice (VGLUT3−/ − ) mice. Sleep/wake stages have been analyzed in wild-type and VGLUT3−/ − mice in different stress conditions: i) Undisturbed condition for 48 hours to monitor the spontaneous sleep-wake cycles; ii) Sleep recovery after an acute stress (restraint stress); and iii) Sleep changes after chronic social defeat stress that induces long lasting social avoidance. Our data suggest that sleep modulation by VGLUT3 neurons depends on the emotional context. These findings should contribute to further understand how neuronal heterogeneity of the raphe network can underlie mood and sleep regulation. References [1] Amilhon B, Lepicard E, Renoir T, Mongeau R, Popa D, Poirel O, Miot S, Gras C, Gardier AM, Gallego J, Hamon M, Lanfumey L, Gasnier B, Giros B, El Mestikawy S (2010) J Neurosci. 30: 2198–210.
S.16.02 Chronotherapeutics to target the biological clock, heal depression and prevent suicide F. Benedetti1 °
1 IRCCS
Ospedale San Raffaele, Milan, Italy
Clock genes bias non-clock brain functions in patients with Bipolar Disorder. Some components of the molecular machinery of the clock also participate in signal transduction pathways regulating core neuronal and glial metabolic functions, and we showed that their genetic variants bias integrity and function of grey and white matter in the brain. Focusing on genetic mutations of CLOCK, we showed that they bias core psychopatological symptoms such as instability of circadian rhythms, insomnia, recurrence of illness. By studying the core negative cognitive biases associated with bipolar depression, we now showed that CLOCK mutants have a worse tendency toward the generalization
across time of negative distortions, worse hopelessness, higher suicidality when depressed, and a dimished resilience as shown by a stroger relationship between early life stress and current suicidality. Chronotherapeutic antidepressant interventions that directly target the CLOCK, such as the combined administration of sleep deprivation and light therapy, cause immediate changes of cortical excitability and neural responses to stimuli, which is paralleled by an immediate decrease of depression and suicidality thus being able to provide an immediate therapeutic effects for the patients. The worse and life-threatening cognitive symptoms, such as suicidal ideation and planning, are the first to disappear in responders, and also show a persistent amelioration in patients who fail to achieve a final response to treatment. These findings suggest that treatments targeting the chronobiology of depression can provide a mean to achieve the yet unmet need of rapidly healing depression and preventing suicide in patients with mood disorders. S.16.03 BDNF, depression and sleep: perspectives from animal models T. Stenberg1 °
1 University
of Helsinki, Helsinki, Finland
Almost all depressive patients suffer from some type of sleep disturbance, often insomnia, but also hypersomnia. Depression also alters the normal characteristic of sleep, as measured using EEG. BDNF is a neurotrophic factor that is involved in regulation of sleep and sleep homeostasis. Restriction of sleep modulates expression of BDNF in several brain areas. As also depression has been shown to modulate BDNF levels, we have studied these connections using two animal models of depression: clomipramine treatment during early development (CLI) and change of pups between mothers. We found that CLI-treated rats in adulthood exhibited a disturbed sleep architecture (REM sleep fragmentation was increased and NREM periods were shorter). BDNF levels in the basal forebrain were reduced. Also sleep homeostasis, as assessed using short-term sleep deprivation (SD), was disturbed in the CLItreated rats: a 3 h SD period induced a smaller increase in the amount of NREM sleep during sleep recovery than in control rats. Moreover, while the basal forebrain BDNF levels decreased during SD in control rats, such a decline was not observed in CLI rats. Epigenetic regulation of BDNF in three brain areas (cortex CX, basal forebrain BF and hypothalamus) was assessed during spontaneous sleep and sleep deprivation. A diurnal variation in Bdnf expression was found in the CX but such variation was not observed in the BF. Also Bdnf p1 methylation levels showed diurnal variation only in the CX. Sleep deprivation induced Bdnf in the CX but not in the BF. S.16.04 Sleep-related neuroplasticity in major depression M. Dresler1 ° 1 Radboud University Medical Center, Nijmegen, The Netherlands Sleep plays an important role in memory processing, however is disturbed in major depression. In a series of studies, we investigated sleep-related neuroplasticity in depressed patients and
S.16. Translational research on sleep and depression
S.16. Translational research on sleep and depression S.16.01 Is the vesicular glutamate transporter type 3 (VGLUT3) a novel marker linking mood to sleep? A study in VGLUT3 deficient mice V. Fabre1 ° , F. Henderson1 , V. Vialou1 , S. El Mestikawy1 Paris Seine NPS − Institut de Biologie Paris Seine IBPS − Sorbonne Universit´es, UPMC UM CR18 − INSERM U1130 − CNRS UMR 8246, Paris, France 1 Neuroscience
Impaired sleep is a symptom that often associates with affective disorders including depression and anxiety. However, the mechanisms underlying both mood and sleep regulation remain to be determined. Thus, sleep profiling in animal models of mood disorders is a critical step to further define the links between sleep and emotional behaviors. Here, we propose to assess sleep and wake regulation in mice lacking the Vesicular Glutamate Transporter Type 3 (VGLUT3). VGLUT3 accumulates glutamate into synaptic vesicles to promote its regulated release. Interestingly, VGLUT3 is present in subclasses of 5-HT neurons and terminals. Recent data have suggested that VGLUT3 positively modulates 5-HT raphe transmission as its absence reduces hippocampal extracellular 5-HT levels [1]. In addition, VGLUT3 deletion promotes a marked increase in anxiety behavior. As decreased serotonergic tone is tightly associated with sleep and mood disorders, we assessed sleep/wake patterns in VGLUT3 knock-out mice (VGLUT3−/ − ) mice. Sleep/wake stages have been analyzed in wild-type and VGLUT3−/ − mice in different stress conditions: i) Undisturbed condition for 48 hours to monitor the spontaneous sleep-wake cycles; ii) Sleep recovery after an acute stress (restraint stress); and iii) Sleep changes after chronic social defeat stress that induces long lasting social avoidance. Our data suggest that sleep modulation by VGLUT3 neurons depends on the emotional context. These findings should contribute to further understand how neuronal heterogeneity of the raphe network can underlie mood and sleep regulation. References [1] Amilhon B, Lepicard E, Renoir T, Mongeau R, Popa D, Poirel O, Miot S, Gras C, Gardier AM, Gallego J, Hamon M, Lanfumey L, Gasnier B, Giros B, El Mestikawy S (2010) J Neurosci. 30: 2198–210.
S.16.02 Chronotherapeutics to target the biological clock, heal depression and prevent suicide F. Benedetti1 °
1 IRCCS
Ospedale San Raffaele, Milan, Italy
Clock genes bias non-clock brain functions in patients with Bipolar Disorder. Some components of the molecular machinery of the clock also participate in signal transduction pathways regulating core neuronal and glial metabolic functions, and we showed that their genetic variants bias integrity and function of grey and white matter in the brain. Focusing on genetic mutations of CLOCK, we showed that they bias core psychopatological symptoms such as instability of circadian rhythms, insomnia, recurrence of illness. By studying the core negative cognitive biases associated with bipolar depression, we now showed that CLOCK mutants have a worse tendency toward the generalization
across time of negative distortions, worse hopelessness, higher suicidality when depressed, and a dimished resilience as shown by a stroger relationship between early life stress and current suicidality. Chronotherapeutic antidepressant interventions that directly target the CLOCK, such as the combined administration of sleep deprivation and light therapy, cause immediate changes of cortical excitability and neural responses to stimuli, which is paralleled by an immediate decrease of depression and suicidality thus being able to provide an immediate therapeutic effects for the patients. The worse and life-threatening cognitive symptoms, such as suicidal ideation and planning, are the first to disappear in responders, and also show a persistent amelioration in patients who fail to achieve a final response to treatment. These findings suggest that treatments targeting the chronobiology of depression can provide a mean to achieve the yet unmet need of rapidly healing depression and preventing suicide in patients with mood disorders. S.16.03 BDNF, depression and sleep: perspectives from animal models T. Stenberg1 °
1 University
of Helsinki, Helsinki, Finland
Almost all depressive patients suffer from some type of sleep disturbance, often insomnia, but also hypersomnia. Depression also alters the normal characteristic of sleep, as measured using EEG. BDNF is a neurotrophic factor that is involved in regulation of sleep and sleep homeostasis. Restriction of sleep modulates expression of BDNF in several brain areas. As also depression has been shown to modulate BDNF levels, we have studied these connections using two animal models of depression: clomipramine treatment during early development (CLI) and change of pups between mothers. We found that CLI-treated rats in adulthood exhibited a disturbed sleep architecture (REM sleep fragmentation was increased and NREM periods were shorter). BDNF levels in the basal forebrain were reduced. Also sleep homeostasis, as assessed using short-term sleep deprivation (SD), was disturbed in the CLItreated rats: a 3 h SD period induced a smaller increase in the amount of NREM sleep during sleep recovery than in control rats. Moreover, while the basal forebrain BDNF levels decreased during SD in control rats, such a decline was not observed in CLI rats. Epigenetic regulation of BDNF in three brain areas (cortex CX, basal forebrain BF and hypothalamus) was assessed during spontaneous sleep and sleep deprivation. A diurnal variation in Bdnf expression was found in the CX but such variation was not observed in the BF. Also Bdnf p1 methylation levels showed diurnal variation only in the CX. Sleep deprivation induced Bdnf in the CX but not in the BF. S.16.04 Sleep-related neuroplasticity in major depression M. Dresler1 ° 1 Radboud University Medical Center, Nijmegen, The Netherlands Sleep plays an important role in memory processing, however is disturbed in major depression. In a series of studies, we investigated sleep-related neuroplasticity in depressed patients and