Orexins / Hypocretins An Introduction

Neuropeptides Orexin A (OrxA) & OrxB Cleaved from the same prepro-Orx (1 gene) Also called Hypocretins (Hcrt 1 & 2) Orexin = stimulate feeding Hypocretin = hypothalamus secretion OrxA = 33 aa OrxB = 28 aa ~50% sequence similarity Excitatory function Prepro-orexin OrxA Neuropeptides OrxB

Orx Synthesis Site Orx neurons: at least 2 distinct populations LH, Perifornical Area (PeF), dorsomedial hypothalamus (DMH) DMH + PeF = Stress or Wakefulness LH = Food or Reward Seeking H and D neurons within LH Depolarized35% or Hyperpolarized20% by leptin Fornix Orx Synthesis Site

Orx Receptors Orx1 receptors Orx2 receptors Gp/q/o → PLC → IP3 → Ca++ DG → PKC \ Excitatory Orx2 receptors Gp/q/o → PLC → IP3 → Ca++ (DG → PKC) Also Excitatory GS → AC → cAMP → PKA → CREB → CRE Gi →X AC Orx Receptors

Orx Synthesis Site Hypothalamic (LH – DMH/PeF) Synthesis Widespread Projection Distribution OrxA and OrxB Orx Synthesis Site

Orx Neurons: Input & Projections

Orx-Receptor Specialized Function OrxA binds Orx1 and Orx2 Equal affinity for Orx1 & 2 OrxB binds Orx2 10x less affinity for Orx1 OrxA & B have equal affinity for Orx2 Orx-Receptor Specialized Function

Orx-Receptor Specialized Function Orx1 and Orx2 may be found together VTADA, raphé5-HT, BLA Orx1 & Orx2 have distinct regional expression Orx1 in LCNE, LDT/PPTACh Orx2 in ARCNPY, TMNHA Orx-Receptor Specialized Function

Orx regulation of Feeding

Orexin →+ Feeding LH → Orx →+ Orx2 →+ Feeding Orx2 in VMH →- Glucoreceptor neurons Glucose →- Orx Orx2 in LH →+ MCH neurons Orx2 in ARC →+ NPY neurons →+ Feeding ARC Leptinfat sensors →+ LH-Orx neurons Leptin →- ARC Leptin sensors Ghrelin →+ ARC Leptin sensors Orexin →+ Feeding

Orx → Food Motivation & Seeking Orx:Orx1→ Hedonic Orx1 reward regulation Orx1 activity in NAc ↑LH Orx when motivation for food is high Expectation Palatable Food Starvation Orx → Food Motivation & Seeking

Orx: Body Weight Orx → ↑Feeding Orx2 confers resistance + ↑Energy expenditure Orx2 → ↓ Body weight Orx2 confers resistance Diet-induced obesity Insulin resistance Type II diabetes Orx → ↑Leptin-induced anorexia and catabolism Orx: Body Weight

Orx regulation of Sleep Orx neurons inactive during sleep DMH/PeF Orx neurons become activated during wakefulness Frequently fire just before waking Cause waking within several seconds Not an “On / Off” Switch ↑Probability of sleep→wake transitions Lengthens periods of wakefulness Orx regulation of Sleep

Orx regulation of Sleep Circadian Input to DMH/PeF from SCN SCN →↑basal excitation during active period DMH/PeF Orx → ↑wake-promoting areas DMH/PeF Orx → ↑Orx1 in LC → ↑NE DMH/PeF Orx → ↑Orx1 in raphé → ↑5-HT DMH/PeF Orx → ↑Orx1 in TMN → ↑HA DMH/PeF Orx → ↑Orx1 in basal forebrain and PPT/LPT → ↑ACh Orx regulation of Sleep

Orx regulation of Sleep Basal Circadian excitation of DMH/PeF Tonic activity is modified intermittently During periods of adaptive behavior Rapid Firing of DMH/PeF Orx stimulates LC → ↑NE; raphé → ↑5-HT; TMN → ↑HA; BF & PPT/LPT → ↑Ach → → ↑ wakefulness For Exploration, Predation, Escape, Reward, Social Interaction, Play, Sex, Grooming Orx regulation of Sleep

Orx regulation of Autonomic Function Link Limbic structures To Orx1&2 in Premotor Autonomic centers ↑Sympathetic Activation ↑ HR and BP ↑ Respiratory function PVN = paraventricular PAG = periaqueductal gray PBN = Parabrachial NTS = Solitary Tract AP = Area Postrema RVLM + RVMM = Respiratory centers Orx regulation of Autonomic Function

Orx and Stress Orx is a pro-Stress modulator DMH/PeF Orx → ↑PVN, BNST an CeA CRF producing areas CRF reciprocally innervates DMH/PeF Orx → ↑ all stress neurotransmitters, neuromodulators, and hormones CRF, ACTH, cortisol (= HPA) sympathetic NS, NE, and Epi (adrenal medulla) LC-NE, raphé-5-HT Orx and Stress

Orx and Stress OrxA in human amygdala maximal during positive emotion, social interaction, and anger Orx1 and Orx2 may have opposite effects Anxiety and Depression Orx1 anxiogenic and pro-depressive Orx2 anxiolytic and antidepressant Acting in Amygdala (BLA & CeA), BNST, Hippocampus (DG & CA1) and VTA/NAc Orx and Stress

Orx regulation of Fear Memory

Orx influencing Reward

Orx influencing Reward Orx facilitates Cognition and Learning Direct connections to mPFC Increase sustained attention Orx1 & Orx2 facilitate Associative Learning Including reward reinforcement Reward is closely associated with Arousal Reward Pathway: VTA and NAc (nucleus accumbens) innervate Orx in the LH Orx influencing Reward

Orx influencing Reward LH Orx reciprocally innervates VTA & NAc Both Orx1 and Orx2 receptors → ↑DA also Orx1 & 2 in raphé5-HT → reward behavior Orx involved in highly motivated reward/ drug seeking Triggered by external cues Requiring a high level of effort Also mediated by CRF and NE All drugs: ETOH, nicotine, cocaine, amphetamine, opiates Orx influencing Reward

Motivational Activation of Orx Orx specifically acts in response to environmental challenges (stressors) to facilitate transitions between contrasting behavioral states Motivational Activation of Orx

Motivational Activation of Orx Orx transform motivational activation into adaptive behavior directed toward managing/exploiting the stress, challenge, or opportunity Motivational Activation of Orx

Motivational Activation of Orx Orx function to facilitate adaptive, highly motivated behavior by coordinating psychological and physiological responses, flexibly integrating neural resources to produce coordination of diverse, contextually appropriate actions Motivational Activation of Orx