Presentation by: Jeffrey L. Barr 2/20/09

Affective/Motivational inputSpatial/Contextual input PL – prelimbic cortex, HF - hippocampal formation, RE-nucleus reuniens, MD- medialdorsal nucleus, ACC-nucleus accumbens, VTA-ventral tegmental area, BLA- basolateral nucleus, INC- insular cortex

 Nucleus accumbens (NAcc) “…site for integration of emotional salience and contextual constraints processed in the amygdala and hippocampus, respectively, and executive/motor plans from the PFC, with the output positioned toward controlling goal-directed behavior.” – Goto and Grace, 2008

 NAcc Subregions  Core – guiding behavior toward a goal based upon learning  Shell – unconditioned reward-seeking behaviors - Have interactions via axon collaterals that extend between them

 mPFC input regulated by presynaptic D 2 R – activated by tonic firing  D 1 R activation by phasic firing potentiates vSUB-NAcc pathway

 Tetanic stimulation of mPFC-NAcc pathway generating LTP, generates LTD in vSUB-NAcc pathway.  Tetanic stimulation of vSUB-NAcc pathway generating LTP, generates LTD in mPFC-NAcc pathway.

 What is the effect of vSUB stimulation on NAcc neurons receiving cortical input?  How is vSUB input affected by the mPFC?

 Adult male Sprague Dawley rats  Anesthetized w/chloral hydrate  NAcc neurons responding to stimulation of PL and fimbria were used.  Extracellular recording

 Tetrodotoxin (TTX): blocks voltage-gated sodium channels  Sulpiride (anti-psychotic) is a selective antagonist of D2-receptors

Hippocampal Fiber Systems  Angular bundle  Fimbria (Red) - fornix (yellow/tan)  Dorsal (purple), ventral (green) commisures

‘Chemotrode’- allows both electrical stimulation and chemical infusion at the same site Rec/D2a Stim Stim/TTX

Prelimbic mPFC NAcc (shell + Some medial core Fimbria

 Evoked spike probabilities = # AP’s / # Stimuli  Change in spike probability = Change in hippocampal input

Baseline Histology 30+ minutes TTX in PL Extracellular recording in NAcc / Input from vSUB and PL

PBS into PL TTX into motor cortex TTX into PL w/o stim.

 PL inactivation attenuates ‘spike firing’ in NAcc  Doesn’t effect baseline firing

Baseline Histology 30+ minutes Fimbria tetanus Extracellular recording in NAcc / Input from vSUB and PL

Baseline Histology 30+ minutes Fimbria tetanus TTX in PL 20 minutes Extracellular recording in NAcc / Input from vSUB and PL

Baseline Histology 30+ minutes Fimbria tetanus TTX in PL 10 minutes Extracellular recording in NAcc / Input from vSUB and PL

 Tetanic stimulation of the fimbria potentiated spike firing in the NAcc  Stimulation before but not after PL inactivation produced LTP  After LTP induction, intact mPFC not required to sustain it, but necessary for initiation.

 Fimbria stimulation produced a bimodal response in vSUB-NAcc pathway: decrease, then sustained increase  Decrease is blocked by systemic sulpiride  Transient activation of D2R on PL afferents blocked?

Baseline Histology 30+ minutes Fimbria tetanus Extracellular Recording in NAcc / Input from vSUB and PL Sulpiride iv. 5 minutes

Baseline Histology 30+ minutes Fimbria tetanus Extracellular Recording in NAcc / Input from vSUB and PL Sulpiride iv. 5 minutes TTX into PL 20 minutes Timeline: Exp. 3

Baseline Histology 30+ minutes Fimbria tetanus Extracellular Recording in NAcc / Input from vSUB and PL Sulpiride i.v. 15 minutes5 minutes TTX Into PL Timeline: Exp. 3

 D2R inactivation had no effect on induction or maintenance of fimbria (vSUB) stimulation induced LTP  In presence of D2R inactivation, PL inactivation reversed vSUB-NAcc LTP (D2R inactivation occurring before induction of LTP)

Timeline: Exp. 4 Baseline Histology 30+ minutes Fimbria tetanus Extracellular Recording in NAcc / Input from vSUB and PL Sulpiride Into NAcc 20 minutes TTX Into PL

A

B

 Direct infusion of sulpiride into NAcc blocked transient decrease in firing after fimbria stimulation, before potentiation  Restored attenuation of potentiation by PL inactivation  No effect of vehicle infusions (not shown)

Initiation of vSUB “drive” of NAcc activity dependent upon mPFC (PL)

mPFC (PL) “not required” following LTP induction, mPFC influence upon vSUB-NAcc pathway dependent on D 2 R

 Contribution of local circuits / interneurons?  Contribution of amygdala?  Hippocampal-NAcc hyperactivity – Schizophrenia (lodge and Grace, 2007)  Disconnection of mPFC (lobotomy)- reduced hyperactive vSUB-NAcc pathway?