Martha L. Escobar

Synaptogenesis of mossy fibers induced by spatial water maze overtraining.

Synaptic plasticity has been proposed as a mechanism underlying learning and memory. Synaptic reorganization of hippocampal mossy fibers has been observed after experimentally induced epilepsy, and after brief high‐frequency activation inducing long‐term potentiation. Furthermore, it has been suggested that synaptic changes in the hippocampus may occur after spatial learning. In this study, by using a zinc‐detecting histologic technique (Timm), we demonstrate a significant increase of mossy fiber terminals in the CA3 stratum oriens region induced by training rats during 3 days in a spatial Morris water maze. In contrast, animals trained for only 1 day and animals that were just allowed to swim or were overtrained in a stress‐motivated inhibitory avoidance task did not show increments of mossy fiber terminals in the stratum oriens. Electron microscopy confirmed that synaptic density of mossy fiber terminals in the stratum oriens increases significantly in water maze overtrained animals compared with the swimming control animals. Taken together, these results suggest that overtraining in a spatial learning task induces mossy fiber synaptogenesis that could be involved in the mechanisms underlying long‐term memory storage. Hippocampus 1999;9:631–636.

Fetal brain grafts induce recovery of learning deficits and connectivity in rats with gustatory neocortex lesion

Three groups of rats showing disrupted taste aversion due to gustatory neocortex lesions, were studied. One group received a transplant of homotopic cortical tissue, another of heterotopic tectal tissue, obtained from 17-day-old fetuses. The third group remained without transplant as a lesioned control group. Comparisons of the taste aversion scores before and after graft, revealed that cortical grafted animals significantly improved the taste aversion, whereas those which received tectal grafts, and the cortical-lesioned controls did not. Moreover, results with horseradish peroxidase (HRP) histochemistry revealed that the homotopic, but not the heterotopic, brain transplants were able to re-establish connections with amygdala and with the ventromedial nucleus of the thalamus areas who normally kept connectivity with the gustatory neocortex. These results support the hypothesis that fetal brain transplants can reestablish cognitive functions, as well as connectivity with its host tissue.

Long-term potentiation in the insular cortex enhances conditioned taste aversion retention.

Long-lasting changes in synaptic strength, such as long-term potentiation (LTP), are thought to underlie memory formation. Recent studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and retention of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce LTP in the IC of adult rats in vivo, as well as, that blockade of N-methyl-D-aspartate (NMDA) receptors disrupts CTA and IC-LTP induction in vivo. Here, we present experimental data showing that induction of LTP in the Bla-IC projection previous to CTA training enhances the retention of this task. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying neocortical LTP may contribute to memory related functions performed by the IC.

In vivo long-term potentiation in the insular cortex: NMDA receptor dependence

It has been demonstrated that the insular cortex (IC) plays an important role in the acquisition and storage of different aversive motivated learning tasks like conditioned taste aversion, spatial maze and inhibitory avoidance. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here, we address this issue by examining the induction of synaptic plasticity, long-term potentiation (LTP) in in vivo preparations. The results showed that high frequency stimulation of the basolateral amygdaloid nucleus (Bla) induced LTP in the IC. The LTP induced by tetanus was blocked by application of the N-methyl-D-aspartate (NMDA) receptor antagonists CPP and MK-801, indicating that NMDA receptors were responsible for its induction. These results suggest that in vivo tetanus induced LTP of the Bla-IC projection is a possible mechanism for the memory-related functions performed by the IC.

The NMDA receptor antagonist CPP impairs conditioned taste aversion and insular cortex long-term potentiation in vivo.

It has been proposed that long-term potentiation (LTP) a form of activity-dependent modification of synaptic efficacy, may be a synaptic mechanism for certain types of learning. Recent studies on the insular cortex (IC) a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce an N-methyl-d-aspartate (NMDA) dependent LTP in the IC of adult rats in vivo. Here we present experimental data showing that intracortical administration of the NMDA receptor competitive antagonist CPP (-3(-2 carboxipiperazin-4-yl)-propyl-1-phosphonic acid) disrupts the acquisition of conditioned taste aversion, as well as, the IC-LTP induction in vivo. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying NMDA dependent neocortical LTP, constitute a possible mechanism for the learning related functions performed by the IC.

Neurotrophins and Synaptic Plasticity

It has been suggested that long-term modifications of synaptic transmission constitute the foundation of the processes by which information is stored in the central nervous system. A group of proteins called neurotrophins are considered powerful molecular mediators in central synaptic plasticity. Among these, brain-derived neurotrophic factor (BDNF) as well as neurotrophin-3 (NT-3) have emerged as having key roles in the neurobiological mechanisms related to learning and memory. In this chapter, we review the studies that have represented a significant step forward in understanding the role played by BDNF and NT-3 in long-term synaptic plasticity. The effects of BDNF and NT-3 on synaptic plasticity can be of a permissive nature, establishing the conditions under which plastic changes can take place, or it may be instructive, directly modifying the communication and morphology of synapses. The actions carried out by BDNF include its capacity to contribute to the stabilization and maturation of already-existing synapses, as well as to generate new synaptic contacts. One important finding that highlights the participation of these neurotrophins in synaptic plasticity is the observation that adding BDNF or NT-3 gives rise to drastic long-term increases in synaptic transmission, similar to the long-term potentiation in the hippocampus and neocortex of mammals. Because neurotrophins modulate both the electrical properties and the structural organization of the synapse, these proteins have been considered important biological markers of learning and memory processes.

In vivo effects of intracortical administration of NMDA and metabotropic glutamate receptors antagonists on neocortical long-term potentiation and conditioned taste aversion

It has been proposed that long-term potentiation (LTP), a form of activity-dependent modification of synaptic efficacy, may be a synaptic mechanism for certain types of learning. Recent studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce an N-methyl-D-aspartate (NMDA) dependent LTP in the IC of adult rats in vivo. Here we present experimental data showing that intracortical administration of the NMDA receptor competitive antagonists CPP (-3(-2 carboxipiperazin-4-yl)-propyl-1-phosphonic acid, 0.03 microg per hemisphere) and AP-5 (D(-)-2-amino-5-phosphonopentanoic, 2.5 microg per hemisphere) disrupt the acquisition of conditioned taste aversion, as well as IC-LTP induction in vivo. In contrast, administration of the metabotropic glutamate receptor antagonist MCPG ((RS)-alpha-methyl-4-carboxyphenylglycine, 2.5 microg per hemisphere) does not disrupt the acquisition of CTA nor IC-LTP induction. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying NMDA-dependent neocortical LTP constitute a possible mechanism for the learning-related functions performed by the IC.

The role of cortical cholinergic pre- and post-synaptic receptors in taste memory formation

A number of studies have implicated cholinergic activity in the mediation of learning and memory processes. However, the specific role of muscarinic receptors in memory formation mechanisms is less known. The aim of the present study is to evaluate the effects of muscarinic antagonist M2 presynaptic receptor, AFDX-116 (0.5mM) and M1 and M3 post-synaptic receptor pirenzepine (100mM), as well as a non-selective muscarinic antagonist, scopolamine (136mM), in the insular cortex (IC) during acquisition and retrieval of conditioned taste aversion (CTA). In addition, we evaluate the effects of those antagonists in cortical ACh release by in vivo microdialysis and the effects on the induction of in vivo LTP in the BLA-IC projection. The results showed that the cortical microinjections of scopolamine and pirenzepine, but not AFDX-116, produced significant disruption in the acquisition of CTA, without effects during retrieval. Microinjections of scopolamine and AFDX-116 produced significant cortical ACh release, while infusions of pirenzepine did not produce any release. Application of scopolamine and pirenzepine diminished induction of LTP in the BLA-IC projection, but not AFDX-116, as compared with vehicle. The induction of BLA-CI LTP seems to be modulated by post-synaptic muscarinic acetylcholine receptors and not by pre-synaptic muscarinic receptors. These results suggest a differential involvement of cholinergic receptors during acquisition and retrieval of aversive memory formation, as well as a differential role of muscarinic receptors in the biochemical and electrophysiological processes that may underlay aversive memory.

In vivo insular cortex LTP induced by brain-derived neurotrophic factor

Recent studies suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in long-term synaptic plasticity in the adult brain. Previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of different aversive learning tasks, have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induces an N-methyl-D-aspartate (NMDA)-dependent form of long-term potentiation (LTP) in the IC of adult rats in vivo. Here, we show that acute intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the Bla-IC projection of anesthetized adult rats. This constitutes an in vivo demonstration of neurotrophin-induced potentiation of synaptic transmission in the neocortex. These findings support the concept that BDNF could be a synaptic messenger involved in activity-dependent synaptic plasticity.

In vivo BDNF modulation of adult functional and morphological synaptic plasticity at hippocampal mossy fibers

Brain-derived neurotrophic factor (BDNF) has been proposed as a key regulator and mediator of long-term synaptic modifications related to learning and memory maintenance. Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit LTP at the dentate gyrus (DG)-CA3 pathway produces mossy fiber structural modifications 7 days after tetanic stimulation. In the present study, we show that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the DG-CA3 projection of anesthetized adult rats. Furthermore, we show that BDNF functional modifications in synaptic efficacy are accompanied by a presynaptic structural long-lasting reorganization at the hippocampal mossy fiber pathway. These findings support the idea that BDNF plays an important role as synaptic messenger of activity-dependent synaptic plasticity in the adult mammalian brain, in vivo.