Neural activity in the noradrenergic locus coeruleus correlates with periods of wakefulness and arousal. However, whether tonic or phasic activity in these neurons is necessary or sufficient to induce behavioral state transitions and promote long-term arousal is unresolved. We used optogenetic tools in mice to demonstrate a frequency-dependent, causal relationship between locus coeruleus firing, cortical activity, sleep-to-wake transitions, and general locomotor arousal. Surprisingly, we also found that sustained, high-frequency stimulation of the locus coeruleus at frequencies 5 Hz and above caused reversible behavioral arrests. These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic over-excitation cause behavioral attacks similar to those observed in neuropsychiatric disorders.
Appetite suppression occurs following a meal and also during conditions when it is unfavorable to eat, such as during illness or exposure to toxins. A brain region hypothesized to play a role in appetite suppression is the parabrachial nucleus (PBN)1-3, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The PBN is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin, as well as lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively4-6. Hyperactivity of the PBN is also thought to cause starvation following ablation of orexigenic agouti-related peptide (AgRP) neurons in adult mice1,7. However, the identities of PBN neurons that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide (CGRP)-expressing neurons in the outer external lateral subdivision of the PBN that project to the laterocapsular division of the central nucleus of the amygdala (CeAlc) as forming a functionally important circuit for the suppression of appetite. Using genetically-encoded anatomical, optogenetic8, and pharmacogenetic9 tools, we demonstrate that activation of PBelo CGRP neurons projecting to the CeAlc suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult AgRP neuron-ablated mice. Taken together, our data demonstrate that this neural circuit from the PBN to CeAlc mediates appetite suppression in conditions when it is unfavorable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.
Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as the main effectors of Hcrt signaling. These results establish the Hcrt-LC connection as a critical integrator-effector circuit that regulates NREM sleep/wake behavior during the inactive period. This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain.ChR2 | norepinephrine | step function opsin T he neural basis of wakefulness and arousal is thought to depend on subcortical populations of "arousal-promoting" nuclei located in the hypothalamus and brainstem (1, 2). Neurons in the lateral hypothalamus that express hypocretins (Hcrts-also called "orexins"), a pair of neuropeptides produced from the same genetic precursor (3, 4), have been proposed to play a key role in stabilizing wake states by directly projecting throughout the brain to other arousal populations (1,5,6). Electrophysiological recordings of Hcrt neurons show that they are relatively silent during sleep compared with wakefulness, with phasic bursts of activity preceding transitions to wakefulness (7,8). Loss-of-function perturbation of the Hcrts or their receptors causes a narcolepsy phenotype (9-11). When centrally administered, the Hcrts increase the time spent awake and decrease nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (12, 13).Although it is evident that Hcrts promote wakefulness and arousal, it is unknown which downstream structures are necessary and/or sufficient to mediate their effects. Hcrt neurons project diffusely throughout the brain (14), and it is possible that their effects on wakefulness are due to widespread, global postsynaptic targets. Alternatively, Hcrts may affect arousal primarily by projecting to key downstream arousal centers. An intriguing possibility is that Hcrt neurons affect wakefulness by projecting to the locus coeruleus (LC), a noradrenergic structure in the brainstem known to promote wakefulness and arousal (15, 16). Indeed, the LC receives the densest afferent projections from Hcrt neurons (14, 17). Application o...
What are they? FOXO proteins are a subgroup of the Forkhead family of transcription factors. This family is characterized by a conserved DNA-binding domain (the 'Forkhead box', or FOX) and comprises more than 100 members in humans, classified from FOXA to FOXR on the basis of sequence similarity. These proteins participate in very diverse functions: for example, FOXE3 is necessary for proper eye development, while FOXP2 plays a role in language acquisition. Members of class 'O' share the characteristic of being regulated by the insulin/PI3K/Akt signaling pathway.
The hypocretins (Hcrts) (also called orexins) are two neuropeptides expressed in the lateral hypothalamus that play a crucial role in the stability of wakefulness. Previously, our laboratory demonstrated that in vivo photostimulation of Hcrt neurons genetically targeted with ChR2, a light-activated cation channel, was sufficient to increase the probability of an awakening event during both slow-wave sleep and rapid eye movement sleep. In the current study, we ask whether Hcrt-mediated sleep-to-wake transitions are affected by light/dark period and sleep pressure. We found that stimulation of Hcrt neurons increased the probability of an awakening event throughout the entire light/dark period but that this effect was diminished with sleep pressure induced by 2 or 4 h of sleep deprivation. Interestingly, photostimulation of Hcrt neurons was still sufficient to increase activity assessed by c-Fos expression in Hcrt neurons after sleep deprivation, although this stimulation did not cause an increase in transitions to wakefulness. In addition, we found that photostimulation of Hcrt neurons increases neural activity assessed by c-Fos expression in the downstream arousal-promoting locus ceruleus and tuberomammilary nucleus but not after 2 h of sleep deprivation. Finally, stimulation of Hcrt neurons was still sufficient to increase the probability of an awakening event in histidine decarboxylase-deficient knock-out animals. Collectively, these results suggest that the Hcrt system promotes wakefulness throughout the light/dark period by activating multiple downstream targets, which themselves are inhibited with increased sleep pressure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.