Abstract
Vital hypothalamic neurons regulating hunger, wakefulness, reward-seeking, and body weight are often defined by unique expression of hypothalamus-specific neuropeptides. Gene-ablation studies show that some of these peptides, notably orexin/hypocretin (hcrt/orx), are themselves critical for stable states of consciousness and metabolic health. However, neuron-ablation studies often reveal more severe phenotypes, suggesting key roles for co-expressed transmitters. Indeed, most hypothalamic neurons, including hcrt/orx cells, contain fast transmitters glutamate and GABA, as well as several neuropeptides. What are the roles and relations between different transmitters expressed by the same neuron? Here, we consider signaling codes for releasing different transmitters in relation to transmitter and receptor diversity in behaviorally defined, widely projecting “peptidergic” neurons, such as hcrt/orx cells. We then discuss latest optogenetic studies of endogenous transmitter release from defined sets of axons in situ, which suggest that recently characterized vital peptidergic neurons [e.g., hcrt/orx, proopiomelanocortin (POMC), and agouti-related peptide (AgRP) cells], as well as classical modulatory neurons (e.g., dopamine and acetylcholine cells), all use fast transmitters to control their postsynaptic targets. These optogenetic insights are complemented by recent observations of behavioral deficiencies caused by genetic ablation of fast transmission from specific neuropeptidergic and aminergic neurons. Powerful and fast (millisecond-scale) GABAergic and glutamatergic signaling from neurons previously considered to be primarily “modulatory” raises new questions about the roles of slower co-transmitters they co-express.
Highlights
CO-TRANSMISSION AND WIDELY PROJECTING NEURONS COORDINATING VITAL BRAIN FUNCTIONS neurons are often classified based on a neurotransmitter they contain (e.g., “cholinergic” or “GABAergic” cells), most if not all neurons contain—and use—more than one neurotransmitter
While neuropeptide Y (NPY) and agouti-related peptide (AgRP) cause feeding and weight gain when artificially infused into the brain, and their expression is regulated by body energy status, the weight loss seen when NPY/AgRP cells are destroyed is recapitulated by targeted deletion of their ability to release GABA, rather than NPY or AgRP (Tong et al, 2008)
Are NPY and AgRP, relatively minor modulators of energy balance, while GABA is the “main” transmitter used by NPY/AgRP cells to drive feeding and weight gain? This does not appear to be the case, since when NPY/AgRP cell terminals are selectively stimulated using optogenetics at a behaviorally crucial projection site, the resulting feeding response can be strongly inhibited by antagonists of either GABA or NPY receptors (Atasoy et al, 2012)
Summary
CO-TRANSMISSION AND WIDELY PROJECTING NEURONS COORDINATING VITAL BRAIN FUNCTIONS neurons are often classified based on a neurotransmitter they contain (e.g., “cholinergic” or “GABAergic” cells), most if not all neurons contain—and use—more than one neurotransmitter. Recent optogenetic studies of peptidergic neurons, reviewed below, showed that these cells release fast transmitters, but have not yet revealed significant postsynaptic electrical effects of endogenously released neuropeptides.
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