Exclusive Postsynaptic Action of Hypocretin-Orexin on Sublayer 6b Cortical Neurons

Abstract

The hypocretin-orexin (hcrt-orx) neurons are thought to maintain wakefulness because their loss results in narcolepsy. This role may be fulfilled by the excitatory action that the hcrt-orx peptide exerts on multiple brainstem and forebrain systems that, in turn, promote cortical activation. Here, we examined whether hcrt-orx may also exert a postsynaptic excitatory action at the level of the cortex, where hcrt-orx fibers project. However, we found that neurons in layers 2-5 in the primary somatosensory cortex (SSp) were unresponsive to hcrt-orx. We then found that although all neurons tested in sublayer 6a were also unresponsive to hcrt-orx, all those tested in sublayer 6b were highly sensitive to the peptide. The sublayer selectivity of hcrt-orx was not restricted to the somatosensory cortex, because it was also found to be present in the primary visual cortex, the motor cortex, and the cingulate cortex. In the SSp, in which the hcrt-orx effect was investigated further, it was demonstrated to be postsynaptic, to result from an interaction with Hcrtr2-OX 2 receptors and to depend on the closure of a potassium conductance. Similar to the selectivity of action in the thalamus, where hcrt-orx excites the nonspecific thalamocortical projection neurons and not the specific sensory relay neurons, here in the cortex, it excites a specific subset of cortical neurons which, through corticocortical projections, may also be involved in promoting widespread cortical activation.

Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy

“…In contrast, direct depolarizing effects were not found in layer V pyramidal cell (8), consistent with the reported lack of hypocretin receptor 2 mRNA in layer V neurons of the cingulate cortex (20,21). Another possible source of hypocretin-responsive inputs is subgriseal layer VII (VIb) (22), which sends a prominent projection to layer I (23). However, this pathway would not seem to be a major contributor to the EPSC response in layer V cells because the effect of hypocretin was almost totally eliminated by thalamic lesions (8).…”

Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX2receptor

“…The high density of [ 3 H]EMPA binding in cortical layer 6 is in good agreement with a previous report showing the exclusive postsynaptic excitatory action of orexin on sublayer 6b cortical neurons via its interaction with OX2 receptors (Bayer et al, 2004). It is interesting to note that the highest binding density in the nucleus accumbens was observed in the shell yet only moderate binding in the core.…”

Discharge of Identified Orexin/Hypocretin Neurons across the Sleep-Waking Cycle

“…In fact, local injections of Orx in the brain have been shown to interrupt sleep and stimulate prolonged active waking (Bourgin et al, 2000;Espana et al, 2001). Given their projections and influence (Peyron et al, 1998;Krout et al, 2003), Orx neurons can directly stimulate cortical activation and muscle tone by directly exciting cortical neurons (Bayer et al, 2004) and motor neurons (Yamuy et al, 2004). Also known to play an important role in energy regulation, they moreover have the capacity to stimulate metabolism in parallel with activity through influences on the sympathetic nervous system, the hypothalamo-pituitary-adrenal axis and hypothalamopituitary-thyroid axis (Ida et al, 2000;Hara et al, 2001;Espana et al, 2003;Monda et al, 2003;Yamanaka et al, 2003).…”