Neuropeptide S Enhances Memory During the Consolidation Phase 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 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 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) CopyrightCopyright © 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 CopyrightCopyright © 2011 American College of Neuropsychopharmacology

Fig S2: No nociceptive difference

NA system and memory Activation of β-adrenergic receptors (G s ) 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 CopyrightCopyright © 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 recognition CopyrightCopyright © 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 CopyrightCopyright © 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

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