Kenneth Sadeghian

Early consolidation of instrumental learning requires protein synthesis in the nucleus accumbens.

It is widely held that long-term memories are established by consolidation of newly acquired information into stable neural representations, a process that requires protein synthesis and synaptic plasticity. Plasticity within the nucleus accumbens (NAc), a major component of the ventral striatum, is thought to mediate instrumental learning processes and many aspects of drug addiction. Here we show that the inhibition of protein synthesis within the NAc disrupts consolidation of an appetitive instrumental learning task (lever-pressing for food) in rats. Post-trial infusions of anisomycin immediately after the first several training sessions prevented consolidation, whereas infusions delayed by 2 or 4 hours had no effect. However, if the rats were allowed to learn the task, the behavior was not sensitive to disruption by intra-accumbens anisomycin. Control infusions into the medial NAc shell or the dorsolateral striatum did not impair learning; in fact, an enhancement was observed in the latter case. These results show that de novo protein synthesis within the NAc is necessary for the consolidation, but not reconsolidation, of appetitive instrumental memories.

N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning

The effect of microinfusion of the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5) into the amygdala, medial prefrontal cortex, and dorsal and ventral subiculum on acquisition of a lever-pressing task for food in rats was examined. Serial transmission between the basolateral amygdala and nucleus accumbens core was also examined in an asymmetric infusion design. AP-5 administered bilaterally into either the amygdala or medial prefrontal cortex markedly impaired learning, whereas administration into the dorsal or ventral subiculum had no effect. Unilateral infusion of AP-5 into either the nucleus accumbens core or amygdala was also sufficient to impair learning. These data provide novel evidence for NMDA receptor-dependent plasticity within corticostriatal networks in the acquisition of appetitive instrumental learning.

Appetitive Instrumental Learning Is Impaired by Inhibition of cAMP-Dependent Protein Kinase within the Nucleus Accumbens

The medium spiny neurons of the nucleus accumbens receive a unique convergence of dopaminergic and glutamatergic inputs from regions associated with motivational, cognitive, and sensory processes. Long-term forms of plasticity in the nucleus accumbens associated with such processes as appetitive learning and drug addiction may require coactivation of both dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptors. This notion implies that an intracellular mechanism is likely to be involved in these long-term neuroadaptive processes. The present series of experiments examined the effects of intra-accumbens microinfusion of protein kinase inhibitors on acquisition of an instrumental task, lever-pressing for food. Male Sprague-Dawley rats were bilaterally implanted with chronic indwelling cannulae aimed at the nucleus accumbens core. Following recovery, animals were food-restricted and subsequently trained for operant responding. The broad-based serine/threonine kinase inhibitor H-7 (5 or 27 nmol per side) dose-dependently impaired learning when infused immediately after testing on days 1-4. Rp-cAMPS, a cAMP-dependent protein kinase (PKA) inhibitor, also impaired learning regardless of whether it was infused immediately before (5 or 20 nmol) or immediately after (10 nmol) testing on days 1-4. Rp-cAMPS (10 nmol) also inhibited learning when infused 1 h after testing, though to a lesser extent than when administered before or immediately after testing. The PKA stimulator Sp-cAMPS (5 or 20 nmol) also impaired learning when infused before testing, suggesting that there is an optimal level of PKA activity required for learning. None of the drugs used produced nonspecific motor or feeding effects. These results provide evidence supporting the involvement of nucleus accumbens PKA in appetitive learning and suggest that this kinase may be involved in long-term changes associated with this and other motivationally based neuroadaptive processes.

Spatial learning and performance in the radial arm maze is impaired after N-methyl-{d}-aspartate (NMDA) receptor blockade in striatal subregions.

These experiments addressed the role of striatal N-methyl-D-aspartate (NMDA) receptors in spatial behavior in the radial arm maze. Rats treated with the NMDA antagonist D-2-amino-5-phosphonopentanoic acid (AP-5) in the nucleus accumbens core, medial caudate, and posterior caudate were all significantly impaired in acquiring the correct spatial responses. In contrast, rats infused with AP-5 in the nucleus accumbens shell showed little impairment. When rats in all groups had learned the maze and were performing at similar levels, AP-5 had relatively little effect except in the posterior caudate group, where errors and trial times were again increased. These findings demonstrate the importance of NMDA receptor-dependent activity within the accumbens and caudate in spatial learning and performance. The neural processes necessary for adaptive spatial learning in complex environments may recruit multiple cortical systems having specialized functions, which in turn are integrated in widespread striatal regions.

Inositol is the water-soluble product of acetylcholine-stimulated breakdown of phosphatidylinositol in mouse pancreas.

The water-soluble products of acetylcholine-stimulated breakdown of phosphatidylinositol in mouse pancreas were analyzed by two different and independent procedures. There was an increased formation of free inositol throughout the period of phosphatidylinositol breakdown; no evidence was obtained for acetylcholine-stimulated formation of either inositol 1,2-cyclic phosphate or inositol 1-phosphate under any of the conditions used. The observations suggest that the acetylcholine-stimulated reaction is phosphatidylinositol → phosphatidic acid + inositol. This might occur by either phospholipase D activity, or through complete or partial reversal of the cytidine nucleotide pathway of phosphatidylinositol biosynthesis.

Central Amygdalar and Dorsal Striatal NMDA Receptor Involvement in Instrumental Learning and Spontaneous Behavior

Glutamate-coded signaling in corticostriatal circuits has been shown to be important in various forms of learning and memory. In the present study, the authors found that N-methyl-D-aspartate (NMDA) receptor antagonism in the central nucleus of the amygdala (CeA) and the posterior lateral striatum (PLS) impaired instrumental conditioning but had no effect in the anterior dorsal striatum. NMDA receptor antagonism in the CeA and PLS also affected spontaneous motor behavior and certain aspects of feeding. The present findings extend knowledge of the dynamic neurophysiological processes, instantiated in a complex neural network, required for instrumental learning in the mammalian brain.

Acetylcholine stimulation of selective increases in stearic and arachidonic acids in phosphatidic acid in mouse pancreas

Abstract During the acetylcholine-stimulated loss of phosphatidylinositol and gain in the level of phosphatidic acid in mouse pancreas, there is a selective increase in stearic and arachidonic acids in phosphatidic acid. The amounts parallel the decrease in phosphatidylinositol, which contains predominantly these two fatty acids. Addition of atropine to stimulated tissue reverses the changes. There is a selective disappearance of the stearoyl, arachidonoyl phosphatidic acid, and phosphatidylinositol increases. The changes support the hypothesis that the 1-stearoyl, 2-arachidonoyl diglyceride backbone of phosphatidylinositol becomes phosphatidic acid during acetylcholine stimulation, and is transformed back to phosphatidylinositol on reversion to the unstimulated state.

Synthesis of CDP-diglyceride from phosphatidylinositol and CMP

A reaction in which CDP-diglyceride and inositol are formed from 1-stearoyl, 2-arachidonoyl phosphatidylinositol and CMP occurs readily in dialyzed microsomal preparations from the mouse pancreas. The reaction is Mn2+-dependent, and it is inhibited by each of the two products, CDP-diglyceride and myoinositol. It is presumed to involve the back-reaction of CDP-diglyceride: inositol phosphatidyltransferase (phosphatidyl-inositol synthetase, EC.2.7.8.11.)

THE MECHANISM OF STIMULATED PHOSPHATIDYLINOSITOL BREAKDOWN

SUMMARY: A reaction in which cytidine 5′-diphosphate (CDP)-diglyceride and inositol are formed from 1-stearoyl, 2-arachidonoyl phosphatidylinositol and cytidine 5′-monophosphate (CMP) occurs readily in dialyzed microsomes from mouse pancreas. The reaction requires Mn 2+ and it is inhibited by each of the two products, CDP-diglyceride and myo-inositol. It is presumed to involve the back-reaction of CDP-diglyceride:inositol phosphatidyltransferase (phosphatidylinositol synthetase) (E.C.2.7.8.11). Evidence from [ 3 H ] cytidine incorporation in intact cells indicates that CDP-diglyceride is the first lipid product of acetylcholine-stimulated breakdown of phosphatidylinositol in mouse pancreas. Inositol has been shown previously to be the water-soluble product. The most likely mechanism for stimulated phosphatidylinositol breakdown is therefore the back-reaction of phosphatidylinositol synthetase - phosphatidylinositol + CMP → CDP-diglyceride + inositol. There appears to be the subsequent formation of phosphatidic acid from CDP-diglyceride.