Organization of hypocretin/orexin efferents to locus coeruleus and basal forebrain arousal‐related structures

Abstract

Hypocretin/orexin neurons give rise to an extensive projection system, portions of which innervate multiple regions associated with the regulation of behavioral state. These regions include the locus coeruleus, medial septal area, medial preoptic area, and substantia innominata. Evidence indicates that hypocretin modulates behavioral state via actions within each of these terminal fields. To understand better the circuitry underlying hypocretin-dependent modulation of behavioral state, the present study characterized the degree to which there exists: 1) lateralization of hypocretin efferents to basal forebrain and brainstem arousal-related regions, 2) topographic organization of basal forebrain- and brainstem-projecting hypocretin neurons, and 3) collateralization of individual hypocretin neurons to these arousal-related terminal fields. These studies utilized combined immunohistochemical identification of hypocretin neurons with single or double retrograde tracing from the locus coeruleus, medial preoptic area, medial septal area, and substantia innominata. Results indicate that approximately 80% of hypocretin efferents to basal forebrain regions project ipsilaterally, whereas projections to the locus coeruleus are more bilateral (65%). There was a slight preference for basal forebrain-projecting hypocretin neurons to be distributed within the medial half of the hypocretin cell group. In contrast, hypocretin neurons projecting to the locus coeruleus were located primarily within the dorsal half of the hypocretin cell group. Finally, a large proportion of hypocretin neurons appear to project simultaneously to at least two of the examined terminal fields. These latter observations suggest coordinated actions of hypocretin across multiple arousal-related regions.

Orexinergic innervation of the extended amygdala and basal ganglia in the rat

“…Published reports from tracing, ultrastructural and chemoarchitectonic studies have shown that the small OX neuronal population emits numerous projections throughout the neuraxis from the olfactory bulb and cerebral cortex to the spinal cord (Broberger et al 1998;Elias et al 1998;Cutler et al 1999;Date et al 1999Date et al , 2000Horvath et al 1999;Nambu et al 1999;Bayer et al 2001;Baldo et al 2003;Caillol et al 2003;Guan et al 2003;Sakamoto et al 2004;España et al 2005;Fadel et al 2005;Kirouac et al 2005;Lee et al 2005;Stoyanova and Lazarov 2005;Balcita-Pedicino and Sesack 2007;Oldfield et al 2007;Shibata et al 2008;Shin et al 2008). These findings were corroborated by evaluations of development (Steininger et al 2004;Steininger and Kilduff 2005) neurophysiological investigations (Bayer et al 2002(Bayer et al , 2004Fadel and Deutch 2002;Martin et al 2002;Zheng et al 2005;Bisetti et al, 2006) and comparative approaches (Iqbal et al 2001;McGranaghan and Piggins 2001;Mintz et al 2001;Moore et al 2001;Novak and Albers 2002;Horowitz et al 2005;Takakusaki et al 2005;S...…”

Mechanism for Hypocretin-mediated sleep-to-wake transitions

“…For example, we found that ipsilateral or contralateral inhibition of LC neurons did not block the effects of unilateral Hcrt stimulation. This may be due to the fact that efferent projections from Hcrt neurons typically project both ipsilaterally and contralaterally to downstream brain regions (39). Therefore, inhibiting the LC only on the ipsilateral or the contralateral side would still allow Hcrt neurons to excite the noninhibited LC.…”

The hypothalamus and the neurobiology of drug seeking

“…Reward and arousal related efferent projections from LH include VTA [60], PFC [93], lateral habenula and locus coeruleus (LC) [94]. LH also sends projections to the midline thalamus including the paraventricular thalamus (PVT) [95,96].…”