Post-Training Memory Processing in Amygdala, Septum and Hippocampus: Role of Benzodiazepine/GABAA Receptors, and their Interaction with other Neurotransmitter Systems

Abstract

Benzodiazepine-like molecules, including diazepam and other benzodiazepines, are found in the brain and are concentrated in synaptic vesicle fractions. Training procedures cause a depletion of these molecules in medial septum, amygdala and hippocampus, suggesting a release of the substances. The intensity of the effect varies with the degree of anxiety or stress associated with the type of learning. Systemic administration of the benzodiazepine receptor antagonist, flumazenil, enhances retention of various behaviors. Post-training intrahippocampal but not intraseptal or intra-amygdala flumazenil facilitates retention of habituation learning. Post-training intrahippocampal, intraseptal or intra-amygdala flumazenil facilitates retention of inhibitory avoidance learning. The effect is counteracted by the GABAA agonist, muscimol, correlates with a reduced sensitivity to muscimol, and is shared by the indirect GABAA antagonist, Picrotoxin. The findings suggest that benzodiazepine/GABAA synapses in the hippocampus regulate memory storage of habituation, and similar synapses in septum, amygdala and hippocampus regulate memory storage of avoidance learning. Studies using localized microinjections of specific receptor agonists and antagonists suggest that GABAA synapses act by inhibiting cells excited by NMDA and muscarinic receptors which are necessary for post-training memory processing. ^-Noradrenergic synapses play a modulatory role. The neurotransmitter receptor interactions are seen in the three structures for inhibitory avoidance, and only in the hippocampus in the case of habituation. This suggests the existence of three separate mechanisms, each involved in the regulation of different aspects or components of memories, all with a similar synaptic arrangement, and all downregulated by benzodizepine/GABAA receptors, probably in response to anxiety levels.

Fear Memory

“…The reliance of conditioned fear on DG neurons shown by Liu et al (352), and then again by Ramirez et al (518), who actually were able to change their valence to an appetitive one, may certainly be taken to agree with, and support the findings that the hippocampal formation is a major site of cellular consolidation of fear behavior (265,272,273,359) as it is for most memories (272,401), and the articles pointing to a key role of the DG in disambiguation or delimitation of memories acquired in the hippocampus proper or elsewhere (585,633). The PL and IL vmPFC circuits of appetitive and fear-motivated cued and contextual conditioning and extinction are strictly superimposed in vmPFC (99).…”

“…Several findings strongly suggest that the BLA is a site of consolidation and storage of the memory for IA in parallel to the hippocampus (63,109,212,273,279). A recent detailed review on the role of the CA1 area and of other brain areas in IA and of the major neurohumoral systems involved has appeared (see Ref.…”

“…These areas include hippocampus, BLA, medial septum, entorhinal, perirhinal, anterior cingulate, retrosplenial, prefrontal and posterior parietal cortex (19,52,53,84,265,273,277,365,444,445,649,678) (FIGURES 1 AND 5). Actually, in the making and in the recall of the memory of many or most tasks, no matter how simple, several brain areas are involved and the wide majority of memories do not depend on just one punctiform brain site.…”

“…It is now widely agreed that the CS-US processing of IA takes place in the CA1 region of the hippocampus; acquisition and posttraining (cellular) consolidation of this task are affected by scores of drugs infused into the dorsal CA1 region neurochemical changes typical of LTP and plastic processes (265,272,273,291,(401)(402)(403), and electrophysiological studies have shown a clear correlation in CA1 between LTP and consolidation during IA (657). The biochemical changes described in CA1 for LTP are basically identical to those observed in the first several hours after IA training (265).…”

“…Parallel processing by widely separate brain structures (93,273,279,291,649) could well be one important evolutionary means of preserving information that a small lesion or impediment (i.e., a tiny clot, a vascular spasm) may otherwise disrupt forever. The strategy behind this is the same that we use when we store information in various different computing devices (our desk computer, our laptop, our cell phone, a tablet, and a pen drive), so all these systems back each other up; if we are prevented from accessing one device, we can always try another one.…”