Orexin/hypocretin modulation of the basal forebrain cholinergic system: Role in attention

Abstract

The basal forebrain cholinergic system (BFCS) plays a role in several aspects of attentional function. Activation of this system by different afferent inputs is likely to influence how attentional resources are allocated. While it has been recognized for some time that the hypothalamus is a significant source of projections to the basal forebrain, the phenotype(s) of these inputs and the conditions under which their regulation of the BFCS becomes functionally relevant are still unclear. The cell bodies of neurons expressing orexin/hypocretin neuropeptides are restricted to the lateral hypothalamus and contiguous perifornical area but have widespread projections, including to the basal forebrain. Orexin fibers and both orexin receptor subtypes are distributed in cholinergic parts of the basal forebrain, where application of orexin peptides increases cell activity and cortical acetylcholine release. Furthermore, disruption of orexin signaling in the basal forebrain impairs the cholinergic response to an appetitive stimulus. In this review, we propose that orexin inputs to the BFCS form an anatomical substrate for links between arousal and attention, and that these interactions might be particularly important as a means by which interoceptive cues bias allocation of attentional resources toward related exteroceptive stimuli. Dysfunction in orexin-acetylcholine interactions may play a role in the arousal and attentional deficits that accompany neurodegenerative conditions as diverse as drug addiction and age-related cognitive decline.

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

“…S1A). HA mRNA was highly enriched in the hypothalamus and the basal forebrain, a site of intense projection from orexinergic neurons (22,23), compared with the rest of the brain (Fig. S1A).…”

Differential Effects of the Dual Orexin Receptor Antagonist Almorexant and the GABAA-α1 Receptor Modulator Zolpidem, Alone or Combined with Ethanol, on Motor Performance in the Rat

“…Selective OXR-1 blockade was reported to reduce the ability of rats to discriminate visual signals in a two-lever sustained attention task (Boschen et al, 2009), and orexin inputs to the basal forebrain cholinergic system have been proposed to represent an anatomical substrate for the link between arousal and attention (Fadel and Burk, 2010). Although the rotarod is not comparable with a classical discrimination task, it is conceivable that rotarod performance requires a substantial level of attention from the rat to maintain stability on the rod, while it is rotating at increasing speed.…”

Motivational activation: a unifying hypothesis of orexin/hypocretin function

“…Orexin administration lengthens, and orexin disruption shortens, continuous periods of wakefulness 3–5 , and loss of orexin neurons or receptors are associated with NC in rodents, dogs and humans 4,6–8 . Orexin projections excite wake-promoting systems, including locus coeruleus (LC) norepinephrine, dorsal raphe serotonin, tuberomammillary histamine and basal forebrain (BF)/brainstem acetylcholine neurons 4,5,9–11 . Orexin neurons are more active during wake than sleep, frequently fire just before waking and cause waking within several seconds when optogenetically stimulated 3,7,12,13 .…”

“…This is achieved via direct projections to medial prefrontal cortex (mPFC), where orexins increase sustained attention 54 , and modulation of BF neurons, facilitating attention by causing mPFC acetylcholine release 9 . However, systemic orexin 1 receptor blockade does not affect attention, instead reducing impulsivity, in a five-choice reaction time task 55 , consistent with a role for orexins in facilitating appetitive motivation.…”