Blanco-Centurion CA, Shiromani PJ (2008) Effects of lesions of three downstream targets of orexin/hypocretin neurons does not support the “flip-flop switch” model. Neuroscience 2008 Abstracts 586.2/SS35. Society for Neuroscience, Washington, DC.
Summary: Hypocretin (HCRT) neurons heavily innervate the cholinergic neurons in the basal forebrain (BF), histamine neurons in the tuberomammillary nucleus (TMN) and the noradrenergic locus coeruleus (LC) neurons, three populations that have traditionally been implicated in arousal. Based on the innervation HCRT neurons may regulate arousal by driving these downstream arousal neurons. Here we directly test this hypothesis by simultaneously lesioning these neurons using three saporin-conjugated neurotoxins. Forty four adult male Sprague-Dawley rats received stereotaxically (under anesthesia) delivered microinjections of three different saporin-conjugated neurotoxins as follows: HCRT2-saporin (250 ng/L in 0.25 µL) to lesion TMN neurons; anti-DBH-saporin (1 μg/μL in 0.25 μL) to destroy noradrenergic LC neurons; and 192-IgG-saporin (2 μg/μL ICV; 3μL) to kill the BF cholinergic neurons. Control rats were injected with pyrogen-free saline solution. Rats that had triple lesion the neuronal loss was as follows: -89.2% of ChAT-BF, -75.4% of ADA-TMN and -93.3% of DBH-LC). Surprisingly, in these rats three weeks after lesion the daily levels of wake were not changed. However, rats with lesions of two (ChAT+LC) or three (Chat+TMN+LC) neuronal populations had fewer arousals (<40sec) and a more stable sleep architecture (fewer transitions between states) compared to non-lesioned saline rats. These results are contrary to predictions of the “flip-flop” model. From these data and evidence from knockout mice, we hypothesize that the LC, histamine TMN, and BF cholinergic neurons serve to rapidly awaken a sleeping brain, and with it turn on cognitive function, attention, vigilance, and if necessary the “flight-or-fight” response. Hyperactivity of these neurons may underlie the hyperarousal in PTSD.
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