Neuropeptides as Primary Mediators of Brain Circuit Connectivity

Abstract

Across sleep and wakefulness, brain function requires inter-neuronal interactions lasting beyond seconds. Yet, most studies of neural circuit connectivity focus on millisecond-scale interactions mediated by the classic fast transmitters, GABA and glutamate. In contrast, neural circuit roles of the largest transmitter family in the brain-the slow-acting peptide transmitters-remain relatively overlooked, or described as "modulatory." Neuropeptides may efficiently implement sustained neural circuit connectivity, since they are not rapidly removed from the extracellular space, and their prolonged action does not require continuous presynaptic firing. From this perspective, we review actions of evolutionarily-conserved neuropeptides made by brain-wide-projecting hypothalamic neurons, focusing on lateral hypothalamus (LH) neuropeptides essential for stable consciousness: the orexins/hypocretins. Action potential-dependent orexin release inside and outside the hypothalamus evokes slow postsynaptic excitation. This excitation does not arise from modulation of classic neurotransmission, but involves direct action of orexins on their specific G-protein coupled receptors (GPCRs) coupled to ion channels. While millisecond-scale, GABA/glutamate connectivity within the LH may not be strong, re-assessing LH microcircuits from the peptidergic viewpoint is consistent with slow local microcircuits. The sustained actions of neuropeptides on neuronal membrane potential may enable core brain functions, such as temporal integration and the creation of lasting permissive signals that act as "eligibility traces" for context-dependent information routing and plasticity. The slowness of neuropeptides has unique advantages for efficient neuronal processing and feedback control of consciousness.

Keywords: arousal; hypocretin; hypothalamus; neural circuit; neuropeptides; orexin.

FIGURE 1

Optogenetic evidence for neuropeptide-mediated neural circuit connectivity. (A) Hypothalamic orexin neuron (OHN) → histamine neuron (HAN) circuit. Top left, example of HAN firing response to optogenetic stimulation of OHNs (blue bar), in the presence and absence of orexin receptor blockers (TCS/SB = OX1 and OX2 receptor antagonists SB334867 and TCS-OX2-29). Top right, the same data plotted across many trials, illustrating glutamate (green) and orexin (red) circuit connectivity (AP/s = action potentials per second). Bottom, a conceptualization of the orexin and glutamate transmission as integral-like and derivative-like parallel signals. Source: Schöne et al., 2014. (B) Circuit between hypothalamic orexin neurons and accumbal D2 neurons. Stimulation of orexin cell axons (blue bar) creates orexin-receptor-blockade-sensitive excitation in the postsynaptic D2 neurons (left column, membrane potential recordings; right column, membrane current recordings). Source: Blomeley et al., 2018. (C) Circuit between hypothalamic orexin neurons and LC noradrenaline neurons, in the presence and absence of glutamate (CNQX = AMPA receptor blocker) and orexin (SB = SB334867 orexin receptor blocker) receptor transmission. Adapted from Sears et al., 2013.