1. Orexins / Hypocretins
An Introduction

2. 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

3. 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

4. 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

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

6. Orx Neurons: Input & Projections

7. 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

8. 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

9. Orx regulation of Feeding

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. Orx regulation of Fear Memory

20. Orx influencing Reward

21. 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

22. 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

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

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

25. 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