Interactions between the hippocampus, prefrontal cortex, and amygdala support complex learning and memory.

One of the guiding principles of memory research in the preceding decades is multiple memory systems theory, which links specific task demands to specific anatomical structures and circuits that are thought to act orthogonally with respect to each other. We argue that this view does not capture the nature of learning and memory when any degree of complexity is introduced. In most situations, memory requires interactions between these circuits and they can act in a facilitative manner to generate adaptive behavior

Attenuation of Stimulated Accumbal Dopamine Release by NMDA Is Mediated through Metabotropic Glutamate Receptors

Electrically stimulated dopamine release from the nucleus accumbens is attenuated following application of N-methyl-d-aspartate (NMDA), which is likely to be mediated indirectly through intermediary neuronal mechanisms rather than by a direct action on dopamine terminals. On the basis of known modulatory processes in nucleus accumbens, the current experiments sought to test whether the effect of NMDA was mediated through cholinergic, GABA-ergic, or metabotropic glutamatergic intermediate mechanisms. Fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in nucleus accumbens of rat brain slices in vitro. Stimulated dopamine release was attenuated by NMDA, confirming previous findings, but this attenuation was unaffected by either cholinergic or GABA-ergic antagonists. However, it was completely abolished by the nonselective group I/II/III metabotropic glutamate receptor antagonist α-methyl-4-carboxyphenylglycine (MCPG) and by the selective group II antagonist LY 341396. Therefore, group II metabotropic glutamate receptors, but not acetylcholine or GABA receptors, mediate the attenuation of stimulated dopamine release caused by NMDA, probably by presynaptic inhibition through receptors located extra-synaptically on dopamine terminals. This provides a plausible mechanism for the documented role of metabotropic glutamate receptor systems in restoring deficits induced by NMDA receptor antagonists, modeling schizophrenia, underlining the potential for drugs affecting these receptors as therapeutic agents in treating schizophrenia

Mechanisms Underlying Neurochemical Changes After Sub-Chronic Phencyclidine Treatment: Clues To The Neuropathology Of Schizophrenia

Dopamine is one of the major neurotransmitters in the mammalian brain and changes in its concentration have been associated with schizophrenia. However, dopamine dysfunction alone cannot account for the genesis of schizophrenia. One unifying theory suggests that there is a disruption of the glutamate-dopamine balance such that glutamate has an effect of increasing dopamine release. Conversely, several studies have reported that the excitatory actions of ionotropic glutamate receptor neurotransmission play an important role in regulating extracellular dopamine levels in the striatum. To understand the potential role of glutamatergic mechanisms in schizophrenia, phencyclidine (PCP), a non-competitive N-methyl-D-aspartic acid receptor (NMDAR) antagonist which models aspects of schizophrenia, was used in the current study. In addition to glutamate, acetyl choline neurotransmission, which is known to modulate dopamine release, also changes after PCP pre-treatment. However, the extent to which PCP modulates cholinergic systems and how such modulation contributes to PCP’s psychotomimetic effects are not fully understood. The current study showed that the mechanism of action of PCP involves NMDAR and nicotinic acetyl choline receptor (nAChR) modulation of dopamine function, specifically in the nucleus accumbens shell. The effects of NMDAR and nAChR activation on dopamine release in the nucleus accumbens were assessed using fast scan cyclic voltammetry (FSCV) in brain slices from rats sub-chronically pre-treated with PCP, an animal model of schizophrenia. NMDA increased basal dopamine release in both pre-treated and non-pre-treated striatal slices, but there was no consistent change in potassium-evoked dopamine release. Moreover, NMDA attenuated electrically stimulated dopamine release, a change which was reversed by metabotropic glutamate receptors 2 and 3 (mGluR2/3) antagonism. This suggests that NMDA augments glutamate release via activation of NMDAR on dopaminergic axon terminals, an effect which is dependent on mGluR 2/3 receptors, and that activation of NMDARs, in turn, increases electrically stimulated dopamine release. The nAChR agonist nicotine and the antagonist dihydro-β-erythroidine hydrobromide (DHβE) both modulated dopamine release in brain slices as well. In addition to studies in brain slice preparations, the effects of PCP on cholinergic and dopaminergic mechanisms were assessed through blood-oxygen-level dependent (BOLD) contrast using pharmacological magnetic resonance imaging (phMRI). Specifically, changes in brain-wide BOLD responses to nicotine and amphetamine administration were assessed before and after either saline or PCP pre-treatment. The results indicated that cholinergic and dopaminergic mechanisms were disrupted by PCP treatment. However, resting state MRI showed that brain resting-state functional connectivity was not altered by PCP pre-treatment. Thus, both in vitro and in vivo experiments suggest that cholinergic systems in nucleus accumbens were partially interrupted by subchronic PCP pre-treatment. Therefore, future studies of the role of dopamine and glutamate in schizophrenia should consider the modulatory role of cholinergic systems. Together, these studies suggest that the cholinergic system in nucleus accumbens may serve as an important therapeutic target for treatment of schizophrenia

Sexually dimorphic muscarinic acetylcholine receptor modulation of contextual fear learning in the dentate gyrus.

Contextual fear conditioning, where the prevailing situational cues become associated with an aversive unconditional stimulus such as electric shock, is sexually dimorphic. Males typically show higher levels of fear than females. There are two components to contextual fear conditioning. First the multiple cues that encompass the context must be integrated into a coherent representation, a process that requires the hippocampus. The second is that representation must be communicated to the basolateral amygdala where it can be associated with shock. If there is inadequate time for forming the representation prior to shock poor conditioning results and this is called the immediate shock deficit. One can isolate the contextual processing component, as well as alleviate the deficit, by providing an opportunity to explore the context without shock prior to the conditioning session. The purpose of the present study was to determine the extent to which cholinergic processes within the dentate gyrus of the hippocampus during contextual processing contribute to the sexual dimorphism. Clozapine-n-oxide (CNO) is a putatively inactive compound that acts only upon synthetic genetically engineered receptors. However, we found that CNO infused into the dentate gyrus prior to exploration eliminated the sexual dimorphism by selectively decreasing freezing in males to the level of females. Biological activity of CNO is usually attributed to metabolism of CNO to clozapine and we found that clozapine, and the muscarinic cholinergic antagonist, scopolamine, produced results similar to CNO, preferentially affecting males. On the other hand, the muscarinic agonist oxotremorine selectively impaired conditioning in females. Overall, the current experiments reveal significant off-target effects of CNO and implicate muscarinic cholinergic receptors in the dentate gyrus as a significant mediator of the sexual dimorphism in contextual fear conditioning

Interactions between the hippocampus, prefrontal cortex, and amygdala support complex learning and memory.

One of the guiding principles of memory research in the preceding decades is multiple memory systems theory, which links specific task demands to specific anatomical structures and circuits that are thought to act orthogonally with respect to each other. We argue that this view does not capture the nature of learning and memory when any degree of complexity is introduced. In most situations, memory requires interactions between these circuits and they can act in a facilitative manner to generate adaptive behavior