Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control

Abstract

Physiological fluctuations in the levels of hormones, nutrients, and gasses are sensed in parallel by interacting control systems distributed throughout the brain and body. We discuss the logic of this arrangement and the definitions of "sensing"; and then focus on lateral hypothalamic (LH) control of energy balance and respiration. LH neurons control diverse behavioral and autonomic processes by projecting throughout the neuraxis. Three recently characterized types of LH cells are discussed here. LH orexin/hypocretin (ORX) neurons fire predominantly during wakefulness and are thought to promote reward-seeking, arousal, obesity resistance, and adaptive thermogenesis. Bidirectional control of ORX cells by extracellular macronutrients may add a new regulatory loop to these processes. ORX neurons also stimulate breathing and are activated by acid/CO 2 in vivo and in vitro. LH melanin-concentrating hormone (MCH) neurons fire mostly during sleep, promote physical inactivity, weight gain, and may impair glucose tolerance. Reported stimulation of MCH neurons by glucose may thus modulate energy homeostasis. Leptin receptor (LepR) neurons of the LH are distinct from ORX and MCH neurons, and may suppress feeding and locomotion by signaling to the mesolimbic dopamine system and local ORX neurons. Integration within the ORX-MCH-LepR microcircuit is suggested by anatomical and behavioral data, but requires clarification with direct assays of functional connectivity. Further studies of how LH circuits counteract evolutionarily-relevant environmental fluctuations will provide key information about the logic and fragilities of brain controllers of healthy homeostasis.

Motivational activation: a unifying hypothesis of orexin/hypocretin function

“…For example, orexin neurons depolarize when blood CO 2 levels rise, causing increased respiration via brainstem projections 33,44 . As with other orexin-dependent behaviors, homeostatic modulation of breathing is conditional, occurring predominantly when animals are awake and active 44 .…”

“…As with other orexin-dependent behaviors, homeostatic modulation of breathing is conditional, occurring predominantly when animals are awake and active 44 . Intriguingly, application of CO 2 to orexin cells reduces their responsiveness to glucose, meaning that at least some orexin cells respond to multiple homeostatic signals, potentially to help prioritize different behavioral strategies (breathing/feeding) on the basis of need hierarchies 33 .…”

“…Orexins and dynorphin can be packaged in the same synaptic vesicles and can have directly opposing electrophysiological and behavioral actions (at least in VTA 55 ). However, orexin and kappa opioid receptors are heterogeneously distributed among synaptic compartments and cell types across target regions, yielding substantial heterogeneity in orexin/dynorphin effects 33,63 . Because most prior experiments have disrupted orexin signaling (for example, with antagonists or receptor/peptide knockout) while sparing dynorphin and other signaling, there is still much to learn about orexin/co-transmitter interactions.…”

“…In addition, at least two subpopulations of orexin neurons (termed H and D neurons) exist 33 . These subtypes vary in their anatomical and electrophysiological characteristics, but not in their likelihood of projecting to LC or VTA or their expression across the mediolateral extent of the orexin field.…”

Peripheral and Central Glucose Sensing In Hypoglycemic Detection

“…Although they clearly appear to serve in this capacity, this may substantially underestimate the contribution of CNS glucose sensors to hypoglycemic counterregulation. Distributing specific glucose sensitivity to peripheral afferents may in fact be essential to allowing central glucose-sensing neurons to serve as metabolic sensors monitoring the overall energy status of the organism during periods of deficit (15,56). Decreasing their sensitivity to any single metabolite may allow these neurons to better detect and integrate a variety of incoming signals to help The model provides for peripheral (PMV and carotid body) and central (hindbrain and hypothalamic) glucose sensory inputs that feed into integrative networks located in the hindbrain and hypothalamus.…”