 Endocannabinoids: Learning, & Memory Clarissa Staton Endocannabinoids Seminar 2015

Why should we care?  Clinical Significance: Dementias!  e.g. Alzheimer’s disease, vascular dementia, etc.  10% of pop. will develop [1]  Currently no cure

What we know  Endocannabinoid system=important for learning and memory  CB1 Receptors But..  What is the specific role of CB1 in learning and memory?

Kuhnert et al., 2013 Background  CB1 agonist=WIN  CB1 antagonist=AM251 Methods  Injections: BLA & mPFC  Fear-Potentiated Startle (FPS) Paradigm

Kuhnert et al.: Memory Consolidation Results  Administration of drug  BLA: Control vs WIN (agonist)  mPFC: Control vs. AM251 (antagonist)

Kuhnert et al.: Memory Retrieval Results  Administration of drug  BLA & mPFC: Control vs WIN (agonist)

 What is the specific role of CB1 in learning and memory?  Consolidation, retrieval, & retrieval memory

What else is know?  Cannabinoid Neurotransmitters: AEA & 2-AG  Signaling terminated by enzymatic hydrolysis  2-AG: hydrolyzed by monoacylglycerol lipase (MGL)

Griebel et al., 2015  Methods  SAR127303=MGL knockout drug  Testing

Griebel et al.: MLG & 2-AG

What still is not known..  2-AG & it’s contribution to cognitive functions  Clinical usage of this knowledge

Kishimoto et al., 2015: Methods  Animals  N=166  3 groups  WT, Het, and MGL KO  Timeline

Kishimoto et al., 2015: Spontaneous Physical Activity Methods  3 hours of taping  Spontaneous behavior recorded

 6 behaviors evaluated  Sig. Diff.  Concluded: normal motor activities for MGL KO Kishimoto et al., 2015: Spontaneous Physical Activity Results

Kishimoto et al., 2015: Morris Swim Maze Methods  Pool with translucent platform & cues  Reference Memory Testing  Acquisition Phase (10 days)  Extinction Phase (5 days)  Reverse Memory Testing  Acquisition Phase (10 trials)  Reversal Phase (5 trials)  Probe-trail

Kishimoto et al., 2015: Morris Swim Maze Results  Escape Latencies Improve Reference Memory Acquisition Phase Reference Memory Extinction Phase  Het & KO Sig longer escape latency

Kishimoto et al., 2015: Morris Swim Maze Results  Swimming paths during extinction sessions  Ext 2: control still preference, Het & KO no preference

Kishimoto et al., 2015: Morris Swim Maze Results Reversal Memory Acquisition Phase Reversal Memory Reversal Phase  Escape Latencies Improve  KO & Het shorter escape latencies

Kishimoto et al., 2015: Novel Object Recognition & Contextual Fear Conditioning Methods Novel Object Recognition  3 days to habituate  Objects  Considered exploring object if.. Contextual Fear Conditioning  Mice in chamber delivered foot shock (US)  Mice placed back in chamber with no foot shock  Videotaped for freezing behavior

Kishimoto et al., 2015: Novel Object Recognition Results  1h: WT & KO more time exploring novel object  24h: KO showed recognition Novel Object Recognition  KO mice slower extinction of fear condition (not sig) Contextual Rear Conditioning

Kishimoto et al., 2015: Trace Eyeblink Conditioning Methods  Wires:  1 deliver US  1 record muscle movement of eyelid  Give shock

Kishimoto et al., 2015: Trace Eyeblink Conditioning Results

Kishimoto et al., 2015: Water- Finding Test Methods  Open field with arm  Explore 3 min  EL, FL, DL

Kishimoto et al., 2015: Water- Finding Test Results  ELs KO shorter  DL KO shorter

Take Home Messages  ECB’s facilitate exploratory behavior  2-AG responsible for motor and spontaneous behavior  2-AG responsible for facilitating the extinction (forgetting) process of spatial memory  CB1 receptors not essential for for extinction of non- motivational learning

References 1. Loy, CT; Schofield, PR; Turner, AM; Kwok, JB (1 March 2014). "Genetics of dementia.". Lancet 383 (9919): 828–40.