Hypocretin Excites Midline Intralaminar Thalamic Neurons

Hypocretin has been shown selectively to depolarize midline-intralaminar thalamic neurons and not sensory thalamic neurons.16 Such specificity is congruent with previous observations that hypocretin fibers avoid specific sensory thalamic nuclei, terminating predominantly in midline-intralaminar nuclei such as rhomboid and central medial.12 Midline-intralaminar nuclei show prominent expression of the hypocretin receptor 2,1718 which is very sensitive to both hypocretin peptides.

Bayer and colleagues examined the electrophysiolgical effects of hypocretin-1 and 2 peptides on thalamic neurons in brain slice with whole cell recording.16 Both peptides potently depolarized neurons in midline-intralaminar nuclei with EC50 less than 20 nanomolar but did not depolarize neurons in sensory thalamic nuclei (Figure 4).

Wakefulness

Figure 3. A schematic depicting hypocretin projections and release in brain areas involved in maintaining wakefulness (Adapted from Sutcliffe and de Lecea, 2002).15 In the thalamus, hypocretin axons predominantly project to midline-intralaminar thalamic nuclei. Prefrontal cortex appears to receive a uniquely heavy hypocretin projection compared to other cortical areas. Hypocretin neurons also project to many lower brain areas involved in wakefulness, including tuberomammilary nucleus (TMN), dorsal raphe nucleus (DRN), locus coeruleus (LC), pontine reticular formation (PRF), and prepontine tegmental area (PPT).

Figure 3. A schematic depicting hypocretin projections and release in brain areas involved in maintaining wakefulness (Adapted from Sutcliffe and de Lecea, 2002).15 In the thalamus, hypocretin axons predominantly project to midline-intralaminar thalamic nuclei. Prefrontal cortex appears to receive a uniquely heavy hypocretin projection compared to other cortical areas. Hypocretin neurons also project to many lower brain areas involved in wakefulness, including tuberomammilary nucleus (TMN), dorsal raphe nucleus (DRN), locus coeruleus (LC), pontine reticular formation (PRF), and prepontine tegmental area (PPT).

Figure 4. Left, hypocretin-2 peptide potently depolarizes an intralaminar thalamic neuron, but it does not change the resting potential of a sensory relay neuron, right (adapted from Bayer et al., 2002).16

The Gq-coupled hypocretin receptor 2 have been shown to depolarize neurons in a number of other brain regions through inhibiting a potassium current open at rest,16,19 by activating a calcium current20 or a nonspecific cation current,21 or stimulating the electrogenic sodium-calcium exchanger.22,23 Bayer and colleagues suggest the former may be responsible for the depolarization seen in midline-intralaminar thalamic neurons.16

Intralaminar Thalamic Neurons

Figure 5. Bath application of hypocretin induces a large increase in spontaneous excitatory postsynaptic currents (sEPSCs) in prefrontal layer V pyramidal neurons. These are mediated by glutamate and are action-potential dependent, as they can be suppressed by TTX. Both hypocretin peptides elicit an increase in sEPSCs, and this increase is much greater in medial prefrontal cortex than in other cortical areas (adapted from Lambe and Aghajanian, 2003).24

Figure 5. Bath application of hypocretin induces a large increase in spontaneous excitatory postsynaptic currents (sEPSCs) in prefrontal layer V pyramidal neurons. These are mediated by glutamate and are action-potential dependent, as they can be suppressed by TTX. Both hypocretin peptides elicit an increase in sEPSCs, and this increase is much greater in medial prefrontal cortex than in other cortical areas (adapted from Lambe and Aghajanian, 2003).24

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