Retrieval and reconsolidation of object recognition memory are independent processes in the perirhinal cortex.

Reconsolidation refers to the destabilization/re-stabilization process upon memory reactivation. However, the parameters needed to induce reconsolidation remain unclear. Here we evaluated the capacity of memory retrieval to induce reconsolidation of object recognition memory in rats. To assess whether retrieval is indispensable to trigger reconsolidation, we injected muscimol in the perirhinal cortex to block retrieval, and anisomycin (ani) to impede reconsolidation. We observed that ani impaired reconsolidation in the absence of retrieval. Therefore, stored memory underwent reconsolidation even though it was not recalled. These results indicate that retrieval and reconsolidation of object recognition memory are independent processes.

Safe taste memory consolidation is disrupted by a protein synthesis inhibitor in the nucleus accumbens shell.

Consolidation is the process by which a new memory is stabilized over time, and is dependent on de novo protein synthesis. A useful model for studying memory formation is gustatory memory, a type of memory in which a novel taste may become either safe by not being followed by negative consequences (attenuation of neophobia, AN), or aversive by being followed by post-digestive malaise (conditioned taste aversion, CTA). Here we evaluated the effects of the administration of a protein synthesis inhibitor in the nucleus accumbens (NAc) shell for either safe or aversive taste memory trace consolidation. To test the effects on CTA and AN of protein synthesis inhibition, anisomycin (100microg/microl) was bilaterally infused into the NAc shell of Wistar rats' brains. We found that post-trial protein synthesis blockade impaired the long-term safe taste memory. However, protein synthesis inhibition failed to disrupt the long-term memory of CTA. In addition, we infused anisomycin in the NAc shell after the pre-exposure to saccharin in a latent inhibition of aversive taste. We found that the protein synthesis inhibition impaired the consolidation of safe taste memory, allowing the aversive taste memory to form and consolidate. Our results suggest that protein synthesis is required in the NAc shell for consolidation of safe but not aversive taste memories, supporting the notion that consolidation of taste memory is processed in several brain regions in parallel, and implying that inhibitory interactions between both taste memory traces do occur.

[Memory-linked morphological changes]. / Cambios morfológicos asociados a la memoria.

INTRODUCTION: It has been suggested that storing information in the brain takes place by means of changes in synaptic communication efficiency, which is known as neuronal plasticity. Plastic events include changes in the function, structure, distribution and number of synapses, and it has been suggested that these plastic events could be related to learning and memory. DEVELOPMENT: In this work we will review some studies that report structural changes in which experience and learning intervene. In particular, structural changes have been observed in a region of the brain called the hippocampus, which plays a crucial role in the learning and memory of spatial tasks. It has been claimed that the appearance of new synapses after learning a spatial task is linked to the formation of long-term memory and that the functioning of NMDA-type glutamate receptors is needed for both learning and the formation of new synapses to take place. CONCLUSIONS: Understanding the cellular mechanisms involved in the formation of memory is of utmost importance to be able to check the memory deficiencies that arise from injuries or as a consequence of old age and neurodegenerative diseases.

[Behavior-immunity relationship: the role of cytokines]. / Relación conducta-inmunidad: el papel de las citocinas.

There are several phenomena in which the immune and the central nervous systems regulate each other. However, their mechanisms are poorly understood. Since cytokines have a central role in the regulation of the immune response, this review describes their participation in two forms of neuro-immune communication, immunomodulation by psychological stress and behavioral conditioning of immune response. The role of cytokines in the endocrine and behavioral effects of acute phase, where cytokines have an effect in functions of the central nervous system, is also reviewed. The effects of psychological stress are described as both immunosuppressing and immunoenhancing. Among them, a relevant immunosuppressing one is the reduction of IL-1, IL-2, and IFN-gamma levels. In contrast, some of the pro-inflammatory effects of stress are mediated by an increase in the levels of IL-6, IL-1, and TNF mediated by the neurotransmitter Substance P. A possible role for IL-1 and IFN-beta as possible messengers in immune regulation by behavioral conditioning is proposed. Pro-inflammatory cytokines in turn can activate the hypothalamus-pituitary-adrenal axis and induce sickness behavior during the acute phase response, during which the parasympathetic nervous system serves as pathway for their detection by the central nervous system. An account is given about recent findings on the regulation of cytokine expression by neurotransmitters from the sympathetic nervous system (epinephrine and norepinephrine), a key piece in all these mechanisms of brain-immune communication. Possible mechanisms and pathways of communication between the brain and the immune system, as well as the possible participation of other cytokines are discussed.

Cortical cholinergic activity is related to the novelty of the stimulus.

A number of studies have related cholinergic activity to the mediation of learning and memory. However, the acetylcholine (ACh) participation has been recently implicated in the early stages of memory formation but not during retrieval. The aim of the present study is to evaluate ACh release in the insular cortex (IC) during presentation of different taste stimuli and during their re-exposition by means of the free-moving microdialysis technique. We evaluated the changes in ACh release when a novel taste, saccharin or quinine was presented to the rat and after several presentations of saccharin. Unilateral microdialysis was performed in the IC 1 h before and 1 h after the presentation of: (1) a familiar stimulus (water), (2) a novel taste (quinine), (3) another novel taste (saccharin), (4) a second presentation, (5) a third presentation, and (6) a fourth presentation of saccharin. The volume consumed by the animals was registered as a behavioral parameter. The ACh levels from the microdialysis fractions were analyzed by an HPLC-ED system. Biochemical results showed a significant increment in the cortical ACh release induced by a novel stimulus compared with the release observed during the presentation of a familiar stimulus. The ACh release observed after several presentations of the stimuli decreased to the same levels as those produced by the familiar taste, indicating an inverse relationship between familiarity and cortical ACh release. These results suggest that the cholinergic system plays an important role in the identification and characterization of different kinds of stimuli.

Differential participation of the NBM in the acquisition and retrieval of conditioned taste aversion and Morris water maze.

Deficits in both learning and memory after lesions of the cholinergic basal forebrain, in particular the nucleus basalis magnocellularis (NBM), have been widely reported. However, the participation of the cholinergic system in either acquisition or retrieval of memory process is still unclear. In this study, we tested the possibility that excitotoxic lesions of the NBM affect either acquisition or retrieval of two tasks. In the first experiment, animals were trained for two conditioned taste aversion tasks using different flavors, saccharine and saline. The acquisition of the first task was before NBM lesions (to test retrieval) and the acquisition of the second task was after the lesions (to test acquisition). Accordingly, in the first part of the second experiment, animals were trained in the Morris water maze (MWM), lesioned and finally tested. In the final part of this experiment, another set of animals was lesioned, then trained in the MWM and finally tested. All animals were able to retrieve conditioned taste aversion (CTA) and MWM when learned before NBM lesions; however, lesions disrupted the acquisition of CTA and MWM. The results suggest that the NBM and cholinergic system may play an important role in acquisition but not during retrieval of aversive memories.

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.

Differential effects of 192IgG-saporin and NMDA-induced lesions into the basal forebrain on cholinergic activity and taste aversion memory formation.

Mnemonic deficits resulting from excitotoxic lesion of the basal forebrain have been classically attributed to the resulting depletion of cortical acetylcholine activity. In this study, we have performed a detailed analysis of the cholinergic status of the insular cortex (IC) following local injections of either 192IgG-saporin (192IgG-sap) or N-methyl-D-aspartate (NMDA) directly into the nucleus basalis magnocellularis (NBM). By means of in vivo microdialysis, we show that the immunotoxin lesion results in an almost complete lack of extracellular acetylcholine release, whereas NMDA-induced lesions result in a marginal reduction in cortical cholinergic activity. Choline-acetyltransferase activity in the IC further confirmed this differential pattern of cortical deafferentation. Surprisingly, however, only NMDA-induced lesions showed a strong disruptive effect upon taste aversion learning whereas no detectable deficits could be found following 192IgG-sap lesions. By combining intrabasal injections of 192IgG-sap with acute pre-training infusions of the cholinergic antagonist scopolamine into the IC, a strong disruption of taste aversion was attained. These results imply that residual cholinergic activity, following 192IgG-saporin lesions, might be still critical for normal cortical mediation of memory processing. They also support the role of basal forebrain in mediating learning and memory processes, and demonstrate that mnemonic deficits resulting from excitotoxic lesions of the basal forebrain are not the sole result of cortical acetylcholine activity hypofunction.

Cholinergic modulation of neostriatal output: a functional antagonism between different types of muscarinic receptors.

It is demonstrated that acetylcholine released from cholinergic interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic RN increase occurs in the whole subthreshold voltage range (-100 to -45 mV), remains in the presence of TTX and Cd2+, and can be blocked by the relatively selective M1,4 muscarinic receptor antagonist pirenzepine but not by M2 or M3 selective antagonists. Cs+ occludes muscarinic effects at potentials more negative than -80 mV. A Na+ reduction in the bath occludes muscarinic effects at potentials more positive than -70 mV. Thus, muscarinic effects involve different ionic conductances: inward rectifying and cationic. The relatively selective M2 receptor antagonist AF-DX 116 does not block muscarinic effects on the projection neuron but, surprisingly, has the ability to mimic agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were attributable to autoreceptor block on cholinergic interneurons. These experiments show distinct opposite functions of muscarinic M1- and M2-type receptors in neostriatal output, i.e., the firing of projection neurons. The results suggest that the use of more selective antimuscarinics may be more profitable for the treatment of motor deficits.

Learning impairment and cholinergic deafferentation after cortical nerve growth factor deprivation.

Cholinergic basal forebrain (CBF ) neurons have been shown to respond in vivo to exogenous administration of NGF. Although neurotrophins and their receptors are widely expressed in the CNS, little data exist for the physiological significance of endogenous neurotrophin signaling in CNS neurons. To test directly whether cortically derived NGF is functionally required for the cholinergic functions mediated by the cerebral cortex, repeated injections of anti-NGF mAbs were locally applied into the insular cortex (IC) of rats. The biochemical results, using an in vivo microdialysis technique, showed a dramatic lack of extracellular release of acetylcholine after high potassium stimulation compared with controls. Furthermore, by using small injections of the neurotracer fluorogold, we found a corresponding disruption in the connectivity between the IC and the CBF. Behavioral experiments showed that the NGF antibodies applied into the IC produced a significant disruption on the acquisition of conditioned taste aversion and inhibitory avoidance learning. However, the same animals were able to recall the taste aversion when the conditioning trial was established before injections of NGF antibodies. Given these results, it seems that cortical cholinergic functions are actively dependent on locally derived NGF in the adult normal brain, and that the cholinergic activity from the CBF is not necessary for recalling aversive stimuli, but is necessary for the acquisition of aversively motivated conditionings.

Insular cortex and amygdala lesions induced after aversive training impair retention: effects of degree of training.

These experiments examined the effects of N-methyl-D-aspartate (NMDA)-induced lesions of the amygdala and insular cortex induced 1 week after rats were trained on a footshock motivated escape task in a two-compartment runway. In the first experiment, male rats were given 10 training trials and, 1 week later, received microinjections of a buffer solution or NMDA into either the insular cortex (IC) or the amygdala (AM). In an inhibitory avoidance retention test 1 week after the microinjections, the retention latencies (i.e., latencies to enter the compartment where shock had been delivered) of both the AM- and "IC-lesioned" groups were significantly lower than those of the buffer-injected groups. Additionally, in comparison with the buffer controls, rats in the two lesioned groups made significantly more crossings between the two compartments during the retention test. In a second experiment, male rats were given 1, 10, or 20 escape training trials 1 week before receiving either sham or NMDA lesions in the IC. The retention test was given 1 week after microinjection. Those sham or lesioned animals that were given only one training trial did not demonstrate retention. Both lesioned groups given 10 or 20 training trials were significantly disrupted on both the step-through latencies, and the number of crossings between the two compartments. The retention-impairing effects of NMDA-induced lesions were slightly attenuated in the group given 20 escape training trials. The findings provide additional evidence that the AM and the IC are involved in regulating the long-term retention of aversively motivated training.

Effects of catecholaminergic depletion of the amygdala and insular cortex on the potentiation of odor by taste aversions.

This experiment examined the effects of catecholamine depletion of the amygdala or insular cortex on the acquisition of olfactory and gustatory learning tasks. Bilateral lesions with 6-hydroxydopamine (4 micrograms/0.5 microliters) were done in either amygdala or insular cortex of Wistar male rats, with two groups receiving sham lesions. All four groups of animals were trained and tested in the potentiation of odor by taste aversion paradigm. The results showed that the amygdala-lesioned group acquired the taste, but not hte odor aversion, while the insular cortex-lesioned group acquired odor, but not taste aversion. Both sham groups showed strong taste and odor aversions. Catecholamine levels in both lesioned groups were significantly lower than those in the sham groups. These results suggest that catecholamines are necessary in the insular cortex for the acquisition of taste and in the amygdala for the acquisition of odor aversion in the potentiation of odor by taste aversion paradigm.

Hypothalamic but not cortical grafts induce recovery of sexual behavior and connectivity in medial preoptic area-lesioned rats.

We have previously shown that hypothalamic fetal brain grafts induced recovery of sexual behavior in medial preoptic area (MPOA)-lesioned male rats. In the present series of experiments, male rats with completely abolished sexual behavior by MPOA lesions received either hypothalamic or frontal cortical fetal grafts. The animals that received hypothalamic grafts showed a gradual recovery of sexual behavior. In contrast, those animals who received cortical grafts did not recover sexual behavior during the 15 weeks after the graft. In addition, to evaluate the connectivity of the grafted tissue with the host brain, a retrograde tracer, fluorogold, was injected in the dorsal tegmental area. Fluorogold-labeled cells were found in the hypothalamic, but not in the cortical grafts. These results suggest that specificity of the grafted tissue and connectivity between brain grafts and host tissue are necessary for the recovery of male sexual behavior in MPOA-lesioned rats.

Fetal brain transplants induce recovery of male sexual behavior in medial preoptic area-lesioned rats.

Male rats received bilateral lesions within the medial preoptic area which completely abolished sexual behavior. Hypothalamic fetal brain transplants gradually restored sexual behavior to prelesion levels by the 6th week after the transplant. Immunocytochemical analyses revealed tyrosine hydroxylase immunoreactivity neurons within the transplanted tissue. These results demonstrate that fetal brain transplants can restore an innate complex behavior in which no spontaneous recovery is observed.

Release of acetylcholine, gamma-aminobutyrate, dopamine and glutamate, and activity of some related enzymes, in rat gustatory neocortex.

The gustatory neocortex (GN), final relay along the gustatory pathway, is a region of the brain involved in the neural integration of feeding behavior. Since information on the neurotransmitters in this nucleus is scarce, the aim of the present work was to establish whether acetylcholine (ACh), gamma-aminobutyric acid (GABA), dopamine and glutamate may act as transmitters within this structure. It was found that GN slices are able to release labeled GABA, ACh and glutamate but not dopamine. Additionally, it was possible to detect significant glutamic acid decarboxylase, choline acetyltransferase and acetylcholinesterase activities in GN homogenates. The activity of the two enzymes involved in acetylcholine metabolism was higher than that observed in other cortical regions. These findings suggest that GABA, ACh and glutamate probably are neurotransmitters in the GN, whereas dopamine is not.

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.