Feeding and wakefulness are circadian rhythms genetically driven by hypothalamic clock mechanisms. The master circadian pacemakers are located in the suprachiasmatic nucleus (SCN) and dorsomedial hypothalamus (DMH). The lateral hypothalamic area (LHA) is a strategic integrative region of feeding and wakefulness. The orexinergic neurons of the LHA receive direct projections from the DMH and, most likely, from the retina through the retinohypothalamic tract (RHT), synchronizing various autonomic, endocrine, and electrophysiological inputs (de Lecea et al., 1998). Because of their rhythmic functional activities, neural SCN/DMN/LHA interactions are endowed with synaptic plasticity (Adamantidis and de Lecea, 2008) modulated by molecular signal/s under the effect of environmental inputs (light/dark) through RHT. The goal of this study is to explore endocannabinoids as best candidates for fine, fast (i.e., nongenomic) and stress-related modulation of circadian feeding and wakefulness functions. Their levels change dramatically in the hypothalamus between the dark and light phases of the day (Kirkham et al., 2000; Valenti et al., 2004; Murillo-Rodriguez et al., 2006). Additionally, blocking CB1 receptors with rimonabant inhibits both food intake and sleep. On the other hand orexin-1, an hypothalamic neuropeptide implicated in the regulation of energy balance and sleep-wakefulness (Rodgers et al., 2002), is synthesized in the LHA neurons innervated by glutamatergic inputs carrying CB1 receptor (Cristino and Di Marzo, SfN 2009). In the present study we examined retinal ganglion cell projections to the brain using intravitreal injection of the anterograde tracer cholera toxin subunit B (CTB), double immunostaining for CB1receptor and CTB in adult C57BL/6J mice manteined on 12:12 light/dark cycle and fed regular chow. We show that CB1-containing nerve fibres not only constitute the major projections to the SCN but have a large terminal field in the LHA. Intense DAGLα expression was found in the cytoplasmic side of plasma membranes in many DMH neurons and in some orexinergic LHA neurons receving RTH projections. We suggest that CB1 might play a neuromodulatory role in the regulation of circadian timing and sleep-wake cycle.

Sleep and metabolism: Shared endocannabinoid and orexin pathways in the mouse hypothalams

FERRANDINO, IDA;
2010

Abstract

Feeding and wakefulness are circadian rhythms genetically driven by hypothalamic clock mechanisms. The master circadian pacemakers are located in the suprachiasmatic nucleus (SCN) and dorsomedial hypothalamus (DMH). The lateral hypothalamic area (LHA) is a strategic integrative region of feeding and wakefulness. The orexinergic neurons of the LHA receive direct projections from the DMH and, most likely, from the retina through the retinohypothalamic tract (RHT), synchronizing various autonomic, endocrine, and electrophysiological inputs (de Lecea et al., 1998). Because of their rhythmic functional activities, neural SCN/DMN/LHA interactions are endowed with synaptic plasticity (Adamantidis and de Lecea, 2008) modulated by molecular signal/s under the effect of environmental inputs (light/dark) through RHT. The goal of this study is to explore endocannabinoids as best candidates for fine, fast (i.e., nongenomic) and stress-related modulation of circadian feeding and wakefulness functions. Their levels change dramatically in the hypothalamus between the dark and light phases of the day (Kirkham et al., 2000; Valenti et al., 2004; Murillo-Rodriguez et al., 2006). Additionally, blocking CB1 receptors with rimonabant inhibits both food intake and sleep. On the other hand orexin-1, an hypothalamic neuropeptide implicated in the regulation of energy balance and sleep-wakefulness (Rodgers et al., 2002), is synthesized in the LHA neurons innervated by glutamatergic inputs carrying CB1 receptor (Cristino and Di Marzo, SfN 2009). In the present study we examined retinal ganglion cell projections to the brain using intravitreal injection of the anterograde tracer cholera toxin subunit B (CTB), double immunostaining for CB1receptor and CTB in adult C57BL/6J mice manteined on 12:12 light/dark cycle and fed regular chow. We show that CB1-containing nerve fibres not only constitute the major projections to the SCN but have a large terminal field in the LHA. Intense DAGLα expression was found in the cytoplasmic side of plasma membranes in many DMH neurons and in some orexinergic LHA neurons receving RTH projections. We suggest that CB1 might play a neuromodulatory role in the regulation of circadian timing and sleep-wake cycle.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/378475
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