Neuropeptide S Enhances Memory During the ConsolidationPhase and Interacts with

Noradrenergic Systems in the Brain

Okamura et. al.Presented by:Justin P. Smith

Intro• Learning: acquisition, consolidation and

retrieval• Inhibitory avoidance (IA)• Object recognition task• NPS precursor transcripts in NA LC– Attention, arousal, stress & memory

Intro cont.

• Role of NPS in aversive (IA) & non-aversive memory tasks (obj recog)

• NPSR KO to assess endogenous NPS signaling• NPS systems interaction with noradrenergic

(NA) system in memory consolidation

Xu et. al. 2004

• Characterized NPS• NPS (icv) ↑ locomotor activity & wakefulness• NPS (icv) increased anxiolytic-effect (open

field, Light-Dark box, EPM, marble burying)• Identified neurons adjacent to NA LC that

express NPS

Rat Brain Schematic

Representative autoradiogram of NPS mRNA expression in LC area

Fig 4 Xu 2004

Fig 8: NPS produces dose-dependent anxiolytic-like effects in C57Bl/6 mice

Duangdao et. al. 2009

• NPSR knockout mice• NPSR KO 12956l/SvEvTac– ↓ arousal – ↓ exploration in novel environment– ↑ anxiety-like behavior– ↑ motor skills performance (rotorod)

Fig 4: NPSR KO mice display increased levels of anxiety-like behaviors

Main Paper• Male C57Bl/6 mice & NPSR KO

12956l/SvEvTac• 12hr light/dark, lights on: 0600• icv injections into lateral ventricle– Verified histologically

• Behavioral tests– IA, Hot-plate Analgesia, Novel object recognition – draw

Fig 1: Dose- and time-dependent enhancement of inhibitory avoidance (IA) memory by neuropeptide S (NPS)Copyright © 2011 American College of Neuropsychopharmacology

Fig S1: Effect of NPS on acquisition and retrieval of IA memory (A) NPS does not appear to modulate memory acquisition(B) NPS appears to attenuate memory retrieval, effect may likely be confounded by the acute anxiolytic properties of NPS

Fig 2: Long-term memory deficits in neuropeptide S receptor (NPSR) knockout (KO) mice

Copyright © 2011 American College of Neuropsychopharmacology

Fig S2: No nociceptive difference

NA system and memory

• Activation of β-adrenergic receptors (Gs) can ↑ memory consolidation in IA

• Blockade of adrenergic receptors prevents consolidation of aversive memory

• Propranolol- β-adrenergic receptor antagonist– i.p. injection post training, 1 nmol i.c.v. NPS 15

min later

• IA measured 48hrs later

Fig 3: Propranolol blocks neuropeptide S (NPS)-induced memory enhancement, adrenergic system helps mediates NPS induced ↑ of aversive memory

Copyright © 2011 American College of Neuropsychopharmacology

Novel object

• Neutral memory task• Fig 4 C57Bl/6– 1nmol NPS i.c.v. 5 min post training (or vehicle)– Vehicle treated unable to discriminate between

objects 48, 96 or 168h

Fig 4: Neuropeptide S (NPS) enhances novel object recognitionCopyright © 2011 American College of Neuropsychopharmacology

Fig S3

Modified Novel Object

• NPSR KO 12956l/SvEvTac favored one object over another identical object in test trials– Novel object (A or B)– Novel place • A in same or different corner

– Novel context• 2 different contexts• AA (context 1) or BB (context 2) or AB’ (different

context)

Fig 5: Impairment of object recognition memory in NPSR KO mice

Copyright © 2011 American College of Neuropsychopharmacology

NPSR KO have novelty induced fear (Duangdao 2009)

Take Home

• Pharmacological & genetic evidence that NPS functions as a memory enhancer– NPS signaling time and dose dependent, acting

during consolidation phase– Retrieval of IA memory ↑ by NPS (possibly by

anxiolytic effects)– Results independent of emotional content (IA vs

novel object)• Novel context recognition, NPSR KO mice

unable to discriminate between objects

Take home cont.

• NPS signaling dose and time dependent– Enhance LTM

• NPSR KO have deficits in LTM• NPS ↑ prolonged arousal that ↑ memory

recall• Once consolidated NPS unable to modify

memory traces• NPS acts similarly/in conjunction to NA system

for memory formation

Thank You