Ramón H. Lima

Parallel memory processing by the CA1 region of the dorsal hippocampus and the basolateral amygdala

There is abundant literature on the role of the basolateral amygdala (BLA) and the CA1 region of the hippocampus in memory formation of inhibitory avoidance (IA) and other behaviorally arousing tasks. Here, we investigate molecular correlates of IA consolidation in the two structures and their relation to NMDA receptors (NMDArs) and β-adrenergic receptors (β-ADrs). The separate posttraining administration of antagonists of NMDAr and β-ADr to BLA and CA1 is amnesic. IA training is followed by an increase of the phosphorylation of calcium and calmodulin-dependent protein kinase II (CaMKII) and ERK2 in CA1 but only an increase of the phosphorylation of ERK2 in BLA. The changes are blocked by NMDAr antagonists but not β-ADr antagonists in CA1, and they are blocked by β-ADr but not NMDAr antagonists in BLA. In addition, the changes are accompanied by increased phosphorylation of tyrosine hydroxylase in BLA but not in CA1, suggesting that β-AD modulation results from local catecholamine synthesis in the former but not in the latter structure. NMDAr blockers in CA1 do not alter the learning-induced neurochemical changes in BLA, and β-ADr blockade in BLA does not hinder those in CA1. When put together with other data from the literature, the present findings suggest that CA1 and BLA play a role in consolidation, but they operate to an extent in parallel, suggesting that each is probably involved with different aspects of the task studied.

ON THE PARTICIPATION OF HIPPOCAMPAL p38 MITOGEN-ACTIVATED PROTEIN KINASE IN EXTINCTION AND REACQUISITION OF INHIBITORY AVOIDANCE MEMORY

Inhibitory avoidance (IA) learning relies on the formation of an association between stepping down from a platform present in a certain context (conditioned stimulus; CS) with an aversive unconditioned stimulus (US; i.e. a footshock). A single CS-US pairing establishes a robust long-term memory expressed as an increase in step-down latency at testing. However, repeated retrieval of the avoidance response in the absence of the US induces extinction of IA memory. That is, recurring presentation of the CS alone results in a new learning indicating that the CS no longer predicts the US. Although the signaling pathways involved in the consolidation of IA and other fear-motivated memories have been profusely studied, little is known about the molecular requirements of fear memory extinction. Here we report that, as happens with its consolidation, extinction of IA long-term memory requires activity of the p38 subfamily of mitogen-activated protein kinases (MAPK) in the CA1 region of the dorsal hippocampus. Moreover, we found that inhibition of hippocampal p38MAPK blocked memory reacquisition after extinction without affecting either the increase in IA memory retention induced by a second training session or animals locomotor/exploratory activity and anxiety state.

Infusion of protein synthesis inhibitors in the entorhinal cortex blocks consolidation but not reconsolidation of object recognition memory

Memory consolidation and reconsolidation require the induction of protein synthesis in some areas of the brain. Here, we show that infusion of the protein synthesis inhibitors anisomycin, emetine and cycloheximide in the entorhinal cortex immediately but not 180 min or 360 min after training in an object recognition learning task hinders long-term memory retention without affecting short-term memory or behavioral performance. Inhibition of protein synthesis in the entorhinal cortex after memory reactivation involving either a combination of familiar and novel objects or two familiar objects does not affect retention. Our data suggest that protein synthesis in the entorhinal cortex is necessary early after training for consolidation of object recognition memory. However, inhibition of protein synthesis in this cortical region after memory retrieval does not seem to affect the stability of the recognition trace.

Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration

Healthy human volunteers 16–82 years of age with at least 10 years of schooling were exposed to two different memory tasks. The first task involved incidental memory. The subjects were asked, as casually as possible: “Did you watch any movie on TV 2 days ago? And 7 days ago? If so, do you remember the title of the movie(s) and the name of the first two actors (actresses)?” Retention scores (maximum = 3: title, actor 1, and actor 2) were equally high (overall mean = 2.6, n = 61) in all age groups (16–20, 21–30, 31–40, 41–60, and 61–82 years) for the day 2 scores. Scores for the movie seen 7 days before decreased significantly and progressively in the three older groups in relation to age, which indicates reduced persistence of this type of memory beginning at the age of 41–50 years and becoming more extensive over the years. The other task was a formal memory procedure. Subjects were asked to study a brief text with factual information on the 1954 World Soccer Cup for 10 min. They were then exposed to 10 questions on the text 2 days and, again, 7 days later. Retention scores declined between the two tests, but in this task, the decline of persistence occurred to a similar extent in all age groups, and thus was not dependent on age. Methylphenidate (10 mg p.o.) given 12 hours after acquisition markedly enhanced persistence of the two memory types. This suggests an involvement of dopaminergic processes in persistence in the late posttraining period.

State-dependent effect of dopamine D1/D5 receptors inactivation on memory destabilization and reconsolidation

Object recognition memories (ORM) can incorporate new information upon reactivation. This update initially involves destabilization of the original memory, which is followed by restabilization of the upgraded engram through a reconsolidation process that requires gene expression and protein synthesis in the hippocampus. We found that when given in dorsal CA1 either immediately after training or 15 min before ORM reactivation in the presence of a novel object, the dopamine D1/D5 receptor antagonist SCH23390 did not affect ORM consolidation, expression or retention but impeded the amnesia caused by the post-retrieval administration of the mRNA synthesis inhibitor α-amanitin or the protein synthesis blocker anisomycin. This anti-amnesic effect was not observed when SCH23390 was given immediately after training and again 15 min before memory reactivation. Our results demonstrate that hippocampal D1/D5 receptors are not needed for formation, retrieval or post-retrieval restabilization of the ORM trace but are essential for its destabilization when reactivation occurs together with the incorporation of new information into the original memory. Importantly, they also suggest that reenactment of the animals post-learning neurochemical milieu at the moment of memory reactivation can be a boundary condition for reconsolidation.

The Role of the Entorhinal Cortex in Extinction: Influences of Aging

The entorhinal cortex is perhaps the area of the brain in which neurofibrillary tangles and amyloid plaques are first detectable in old age with or without mild cognitive impairment, and very particularly in Alzheimers disease. It plays a key role in memory formation, retrieval, and extinction, as part of circuits that include the hippocampus, the amygdaloid nucleus, and several regions of the neocortex, in particular of the prefrontal cortex. Lesions or biochemical impairments of the entorhinal cortex hinder extinction. Microinfusion experiments have shown that glutamate NMDA receptors, calcium and calmodulin-dependent protein kinase II, and protein synthesis in the entorhinal cortex are involved in and required for extinction. Aging also hinders extinction; it is possible that its effect may be in part mediated by the entorhinal cortex.

Nicotine modulates the long-lasting storage of fear memory

Late post-training activation of the ventral tegmental area (VTA)-hippocampus dopaminergic loop controls the entry of information into long-term memory (LTM). Nicotinic acetylcholine receptors (nAChR) modulate VTA function, but their involvement in LTM storage is unknown. Using pharmacological and behavioral tools, we found that α7-nAChR-mediated cholinergic interactions between the pedunculopontine tegmental nucleus and the medial prefrontal cortex modulate the duration of fear-motivated memories, maybe by regulating the activation state of VTA-hippocampus dopamine connections.

The differential mice response to cat and snake odor

Studies from the last two decades have pointed to multiple mechanisms of fear. For responding to predators, there is a group of highly interconnected hypothalamic nuclei formed by the anterior hypothalamic nucleus, the ventromedial hypothalamic nucleus and the dorsal premammillary nucleus—the predator-responsive hypothalamic circuit. This circuit expresses Fos in response to predator presence or its odor. Lesion of any component of this system blocks or reduces the expression of fear and consequently defensive behavior when faced with a predator or its cue. However, most of the knowledge about that circuit has been obtained using the rat as a model of prey and the cat as a source of predator cues. In the present study, we exposed mice to strong cat or snake odors, two known mice predators, and then we used the rat exposure test (RET) to study their behavior when confronted with the same predators odor. Our data point to a differential response of mice exposed to these odors. When Swiss mice were exposed to the cat odor, they show defensive behavior and the predator-responsive hypothalamic circuit expressed Fos. The opposite was seen when they faced snakes odor. The acute odor exposure was not sufficient to activate the mouse predator-responsive hypothalamic circuit and the mice acted like they were not in a stressful situation, showing almost no sign of fear or defensive posture. This leads us to the conclusion that not all the predator cues are sufficient to activate the predator-responsive hypothalamic circuit of mice and that their response depends on the danger that these predators represent in the natural history of the prey.

Alpha-Tocopherol Counteracts Cognitive and Motor Deficits Induced by Repeated Treatment with Reserpine

Previous studies showed that chronic administration of the monoamine depleting agent reserpine in low doses promotes progressive cognitive and motor impairments in rats, and this protocol has been used as a pharmacological progressive model of Parkinsons disease. These behavioral alterations are accompanied by increased brain oxidative stress. We aimed to verify the effects of the concomitant treatment with the antioxidant agent alpha-tocopherol on the motor and cognitive deficits induced by chronic reserpine in rats. Rats were repeatedly treated with 0.1 mg/kg reserpine with or without a concomitant treatment with 40 mg/kg alpha-tocopherol. Across the treatment, motor and cognitive performances were evaluated by the catalepsy and novel object recognition tests, respectively. As expected, reserpinetreated rats showed progressively increased duration of catalepsy together with short-term memory deficits in the object recognition test. Importantly, these detrimental outcomes due to reserpine treatment were prevented by concomitant daily administration of the antioxidant agent alpha-tocopherol. The results show a preventive role of alpha-tocopherol on behavioral alterations induced by repeated reserpine treatment. This is relevant to the investigation of possible neuroprotective interventions in Parkinson’s disease.

Extinction learning: neurological features, therapeutic applications and the effect of aging

Extinction learning consists of the usually gradual inhibition of the retrieval of a previously learned response or behavior. It is widely used for the treatment of syndromes of learned fear, such as phobias and post-traumatic stress disorder. It relies on well-identified molecular processes in the hippocampus, basolateral amygdala, ventromedial prefrontal cortex (vmPFC) and entorhinal cortex. In humans, thickness of the orbital cortex, vmPFC and the anterior cingulate cortex correlates with the capacity to extinguish. The three regions are functionally inter-related (see below). The development of learned fear syndromes in humans is viewed by many as being due to a deficit of extinction, and so of the capacity to deal with fear. Blockade of NMDA receptors, inhibition of protein synthesis in the vmPFC or blockade of protein synthesis or of various molecular signaling cascades in the hippocampus, amygdala or entorhinal cortex impairs extinction. d-cycloserine, a partial agonist at NMDA receptors, enhances ...