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.

Figure 1. Examples of orexin innervation of cholinergic and GABAergic neurons of the basal forebrain

All photomicrographs were taken from the ventral pallidum/substantia innominata region of the adult (age 3 months) rat basal forebrain (D), following dual-color immunoperoxidase histochemistry using previously described methods [41,45]. A–C. Double-labeling for ChAT (light brown cell body) and orexin A (black fibers). Arrows indicate points of putative appositional contact between orexin fibers and a cholinergic neuron. Scale bar represents approximately 25 μm. B and C show different focal planes from the same region, indicating multiple putative z-plane contacts on the proximal dendrite (B) and soma (C) of the same neuron. E. Double-labeling for the calcium-binding protein parvalbumin (light brown cell bodies), which marks a subset of GABAergic corticopetal basal forebrain neurons, and orexin A (black fibers). Again, orexin fibers are found in high abundance in this region of the basal forebrain, including on and around GABAergic neurons.

Figure 2. Activation of orexin neurons by FG-7142

Adult male rats were treated acutely with the anxiogenic benzodiazepine partial inverse agonist FG-7142 (8.0 mg/kg; i.p.) or vehicle and sacrificed two hours later. Brains were processed for double-label immunohistochemistry for Fos (black nuclei) and orexin (light brown cytoplasmic staining) using previously-described methods [40,100]. Few double-labeled cells are seen following vehicle treatment (A). FG-7142 treatment (B) produced a robust activation of perifornical orexin neurons as seen in this cluster of double-labeled cells (arrows). Scale bar represents approximately 100 μm.

Figure 3. Effects of orexin-1 receptor blockade on attentional performance

The figure depicts the significant effects of systemic (A) or intrabasalis (B) SB-334867 in an attention-demanding task that required discrimination of brief visual signals from trials with no signal presentation. Systemic SB-334867 (5.0 mg/kg; i.p.) significantly decreased signal detection following the 500-ms signal (relative hits; denoted by the asterisk), effects similar to those observed following loss of basal forebrain corticopetal cholinergic inputs [76,79]. Intrabasalis SB-334867 (60 μg) decreased accuracy on a sustained attention (SAT) measure, that takes into account accuracy on trials with and without signal presentation (denoted by the asterisk). This decrease in overall accuracy may reflect that SB-334867 also affected noncholinergic basal forebrain corticopetal cholinergic neurons [20,117]. The figure is modified from Boschen et al. [14]. Error bars represent SEMs.

Figure 4. Hypothetical summary model of orexin regulation of cholinergic projections to prefrontal (PFC) and insular (IC) cortices, based on known anatomical relationships

ACh neurons from the basal forebrain cholinergic system (BFCS) have widespread cortical projections, including to PFC and IC. The involvement of the PFC in executive function and the putative role of the IC as “interoceptive cortex” suggests that the BFCS may influence exteroceptive and interoceptive attention via projections to these areas, respectively. Orexin neurons of the lateral hypothalamus and perifornical area (green stars), as integral components of the hypothalamic circuitry responsive to physiological signals, may allow for coordinated activation of rostral attentional circuitry, ultimately allowing for biased allocation of attentional resources toward stimuli related to physiological status. Alterations in these interactions may contribute to a number of neuropsychiatric conditions in which individual components of these pathways have been implicated, including drug addiction or relapse and the anorexia of aging.