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Review
. 2017 Jan 31:11:10.
doi: 10.3389/fnbeh.2017.00010. eCollection 2017.

Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention

Ines Villano  1 , Antonietta Messina  1 , Anna Valenzano  2 , Fiorenzo Moscatelli  3 , Teresa Esposito  1 , Vincenzo Monda  1 , Maria Esposito  4 , Francesco Precenzano  4 , Marco Carotenuto  5 , Andrea Viggiano  6 , Sergio Chieffi  2 , Giuseppe Cibelli  2 , Marcellino Monda  1 , Giovanni Messina  7
Affiliations
Review

Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention

Ines Villano et al. Front Behav Neurosci. .

Abstract

The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity.

Keywords: acetylcholine; attention; basal forebrain; lateral hypothalamus; orexin.

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Figures

Figure 1
Figure 1
Overview of the basal forebrain (BF) cholinergic pathway. The BF cholinergic system of the Sprague-Dawley rats includes the medial septum (MS), vertical limbs of the diagonal band of Broca (vDB), nucleus basalis of Meynert (NBM), and substantia innominate (SI). The vDB and NBM have diffuse projections to all parts of the neocortex and to basolateral amygdala and olfactory bulb (these latter two are not shown here). The MS and vDB project to hippocampus. Besides, the brainstem cholinergic system projects to the thalamus and hypothalamus but also to the BF region. This system includes the pedunculopontine tegmental nucleus (PPT) and laterodorsal pontine tegmentum (LDT).
Figure 2
Figure 2
Regulation of orexin neurons. Orexin neurons activity is controlled by positive and negative feedback mechanisms mediated by neurotransmitters released by lateral hypothalamus/perifornical area (LH/PFA) neurons. Orexin neurons corelease excitatory neurotransmitters orexin and inhibitory transmitters dynorphin (Dyn) and nociceptin/orphanin FQ (N/OFQ). (A) Direct effect: all of neurotransmitters coreleased by Orexin neurons form a feedback which directly affects postsynaptic orexin neurons. (B) Synaptic modulation: orexins modulate presynaptic glutamate release at excitatory synapses. Besides, Dyn attenuates glutamate release acting on presynaptic excitatory terminals, while N/OFQ inhibits both excitatory and inhibitory transmission. The balance between the excitatory and inhibitory effects determines the activity levels of the postsynaptic cell. (C) Indirect effects: Regulation of orexin neurons by astrocytes: Glutamate activates astrocytes which release lactate (Lac) and protons (H+) into the extracellular space through monocarboxylate transporters (MCTs). Orexin neurons metabolize astrocyte-derived lactate as an energy substrate to sustain activity. Furthermore, extracellular pH decreases due to MCT activity resulting in depolarization of orexin neurons. (D) Adenosine triphosphate (ATP) effects: ATP released by astrocytes and neurons, stimulates orexin neurons depolarizing them through the ionotropic P2X receptors. Ectonucleotidases hydrolyze ATP releasing into adenosine in the extracellular space which inhibits orexin neurons. (E) Autoinhibition: the glutamate released synaptically creates a negative feedback loop acting on presynaptic autoreceptors to inhibit glutamate release. (F) Melanin concentrating hormone (MCH) neurons are directly depolarized by Orexin A and B which stimulate presynaptic glutamate release, whereas dynorphin and N/OFQ induce direct hyperpolarization of MCH neurons. (G) Leptin receptor-expressing GABAergic neurons are excited by leptin and use GABA as a neurotransmitter. Leptin inhibits indirectly orexin neurons by activating these inhibitory LepRb+ neurons. In summary, the balance between the excitatory and inhibitory effects determines the activity levels of the orexin neurons. Glut, glutamate; (+), stimulation; (−) inhibition.
Figure 3
Figure 3
Pathways through which orexin could activate the BF to promote attention. In response to salient stimuli, orexin neurons produce several neuropeptides which promote cortical activation and attention by acting on cholinergic and non-cholinergic neurons. Arrows indicate excitatory inputs; dots indicate inhibitory inputs.
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