Carmen Sandi

Experience-dependent Facilitating Effect of Corticosterone on Spatial Memory Formation in the Water Maze

Stress‐related adrenal steroid hormones modulate brain and cognitive function. Electrophysiological studies, including primed burst potentiation and long‐term potentiation, have indicated concentration‐dependent inverted U‐shape effects of corticosterone in hippocampal function and plasticity. Here, we explored the role of corticosterone in the consolidation and long‐term retrieval of spatial learning in the Morris water maze task in rats. We postulated that corticosterone actions might be experience‐dependent with regard to stimulus intensity, such as differential water temperatures. Indeed, rats trained at 19°C showed a quicker rate of acquisition and better long‐term retention than rats trained at 25°C water. In addition, post‐training corticosterone levels, on the first training day, were significantly higher in rats in the 19°C group than in the 25°C group. Performance of rats trained at 25°C, but not at 19°C, water was improved by injecting them i.p. with corticosterone immediately after each training session. Thus, the effect of exogenously administered corticosterone appears to be experience‐dependent, with the experience‐induced corticosterone concentrations as a critical factor determining the cognitive consequences of steroid treatment. Therefore, this work indicates a facilitating corticosterone action, during the post‐training period, on the neural mechanisms determining the strength of information storage under acute, physiological conditions.

Stress and memory: behavioral effects and neurobiological mechanisms

Stress is a potent modulator of learning and memory processes. Although there have been a few attempts in the literature to explain the diversity of effects (including facilitating, impairing, and lack of effects) described for the impact of stress on memory function according to single classification criterion, they have proved insufficient to explain the whole complexity of effects. Here, we review the literature in the field of stress and memory interactions according to five selected classifying factors (source of stress, stressor duration, stressor intensity, stressor timing with regard to memory phase, and learning type) in an attempt to develop an integrative model to understand how stress affects memory function. Summarizing on those conditions in which there was enough information, we conclude that high stress levels, whether intrinsic (triggered by the cognitive challenge) or extrinsic (induced by conditions completely unrelated to the cognitive task), tend to facilitate Pavlovian conditioning (in a linear-asymptotic manner), while being deleterious for spatial/explicit information processing (which with regard to intrinsic stress levels follows an inverted U-shape effect). Moreover, after reviewing the literature, we conclude that all selected factors are essential to develop an integrative model that defines the outcome of stress effects in memory processes. In parallel, we provide a brief review of the main neurobiological mechanisms proposed to account for the different effects of stress in memory function. Glucocorticoids were found as a common mediating mechanism for both the facilitating and impairing actions of stress in different memory processes and phases. Among the brain regions implicated, the hippocampus, amygdala, and prefrontal cortex were highlighted as critical for the mediation of stress effects.

Stress, cognitive impairment and cell adhesion molecules

Stress has profound effects on brain structure and function, but the underlying mechanisms are still poorly understood. Recent studies imply that neuronal cell adhesion molecules of the immunoglobulin superfamily — NCAM and L1 — are important mediators of the effects of stress on the brain. Chronic stress regimes that lead to hippocampal atrophy and spatial-learning impairment in rodents simultaneously induce a pattern of changes in cell adhesion molecule expression that fits with a role for these molecules in stress-induced neuronal damage and neuroprotective mechanisms. These findings highlight cell adhesion molecules as potential therapeutic targets to treat stress-related cognitive disturbances.

Corticosterone enhances long-term retention in one-day-old chicks trained in a weak passive avoidance learning paradigm

Glucocorticoids are released during learning situations and can trigger neural actions through binding to receptors in different brain areas. The possible role of a glucocorticoid action in long-term memory formation was studied, in day-old chicks, by using a passive avoidance task which chicks otherwise only retain for a few hours (< 10) after training. Thus, we examined the effects of intracerebral corticosterone administration on retention 24 h posttraining. The results showed that chicks injected with corticosterone (1 microgram) at either 15 min pretraining or at 5, 30, 60 min (but not 120, 180, or 360 min) posttraining retained the passive avoidance response when tested 24 h posttraining. Studies with specific mineralocorticoid or glucocorticoid receptor antagonists (RU 28318 or RU 38486, respectively) indicated that this increase in retention by corticosterone might be mediated through glucocorticoid receptors. In order to assess whether the facilitatory effect of corticosterone was mediated through an effect on protein synthesis mechanisms, the protein synthesis inhibitor anisomycin was administered prior to corticosterone. However, this treatment only partially attenuated the effect of the steroid, suggesting that corticosterone may influence other cellular processes involved in the formation of long-term memory for the avoidance behaviour.

Abnormal fear conditioning and amygdala processing in an animal model of autism

A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plasticity in the lateral amygdala by means of in vitro single-cell electrophysiological recordings. VPA-treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish. On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused by the hyperreactivity and hyperplasticity found in the lateral amygdala, which may in turn be due to a deficit in the inhibitory system of the amygdala. We hypothesize an ‘aversive world’ syndrome that could, even if not a primary cause of the disorder itself, underlie some core symptoms in autism, such as impairments in social interactions and resistance to rehabilitation.

Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, its polysialylation, and L1

Chronic stress has been shown to induce time-dependent neurodegeneration in the hippocampus, ranging from a reversible damage to a permanent neuronal loss. This damage has been proposed to impair cognitive function in hippocampus-dependent learning tasks. In this study, we have used a 21-day restraint stress procedure in rats, previously reported to induce reversible atrophy of apical dendrites of CA3 pyramidal cells, to assess whether it may influence subsequent performance in the contextual fear conditioning task under experimental conditions involving high stress levels (1 mA shock intensity as the unconditioned stimulus). In addition, we were interested in the study of the possible cellular and molecular mechanisms involved in the reversible phase of neural damage. Cell adhesion molecules of the immunoglobulin superfamily, such as the neural cell adhesion molecule and L1, are cell-surface macromolecules that, through their recognition and adhesion properties, regulate cell-cell interactions and have been reported to play a key role in cognitive functioning. A second aim of this study was to evaluate whether chronic stress would modulate the expression of the neural cell adhesion molecule, its polysialylation, and L1 in the hippocampus. The results showed that chronic stress facilitated subsequent contextual fear conditioning. They also showed that chronically stressed rats displayed reduced hippocampal neural cell adhesion molecule, but increased polysialylated expression as well as a trend towards exhibiting increased L1 expression. In summary, these results support the view that a 21-day chronic stress regimen predisposes individuals to develop enhanced contextual fear conditioning responses. They also indicate that cell adhesion molecules might play a role in the structural remodelling that occurs in the hippocampus as a consequence of chronic stress exposure.

Novelty‐related Rapid Locomotor Effects of Corticosterone in Rats

Glucocorticoids modulate brain function and behaviour through different mechanisms. Although classical effects are mediated through intracellular receptors that modulate gene transcription, recent evidence supports the existence of rapid, nongenomic steroid effects through the neuronal membrane. In this study, we explored possible rapid behavioural effects of corticosterone in the rat, which could provide a model to characterize further the mechanisms involved in rapid corticosteroid nongenomic actions. We found that a corticosterone injection, at doses (2.5 or 5 mg/kg) that mimic plasma concentrations produced by substantial stress, rapidly increases (within 7.5 min of its systemic administration) the locomotor response displayed by rats in a novel environment (activity cage). A lower dose of 1 mg/kg failed to induce this effect. In addition, corticosterone failed to increase locomotion when administered to rats that had been previously exposed to the activity cage. Corticosterone‐induced increased locomotion in a novelty situation was not counteracted by either the intracerebroventricular administration of the protein synthesis inhibitor cycloheximide, or by the intracerebroventricular administration of specific antagonists for each type of intracellular corticosteroid receptor, i.e. RU28318, a mineralocorticoid receptor antagonist and RU38486, a glucocorticoid receptor antagonist. Further studies supported the viability of the receptor antagonists to display an anti‐corticosteroid action interfering, as previously reported, with the behavioural swimming test. Therefore, the rapid actions of corticosterone in locomotor activity described here, which appear to be nongenomic, might provide a model for future research on the elucidation of the mechanisms involved in steroid‐membrane interactions.

Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities

Chronic stress and spatial training have been proposed to affect hippocampal structure and function in opposite ways. Previous morphological studies that addressed structural changes after chronic restraint stress and spatial training were based on two-dimensional morphometry which does not allow a complete morphometric characterisation of synaptic features. Here, for the first time in such studies, we examined these issues by using three-dimensional (3-D) reconstructions of electron microscope images taken from thorny excrescences of hippocampal CA3 pyramidal cells. Ultrastructural alterations in postsynaptic densities (PSDs) of thorny excrescences receiving input from mossy fibre boutons were also determined, as were changes in numbers of multivesicular bodies (endosome-like structures) within thorny excrescences and dendrites. Quantitative 3-D data demonstrated retraction of thorny excrescences after chronic restraint stress which was reversed after water maze training, whilst water maze training alone increased thorny excrescence volume and number of thorns per thorny excrescence. PSD surface area was unaffected by restraint stress but water maze training increased both number and area of PSDs per thorny excrescence. In restrained rats that were water maze trained PSD volume and surface area increased significantly. The proportion of perforated PSDs almost doubled after water maze training and restraint stress. Numbers of endosome-like structures in thorny excrescences decreased after restraint stress and increased after water maze training. These findings demonstrate that circuits involving contacts between mossy fibre terminals and CA3 pyramidal cells at stratum lucidum level are affected conversely by water maze training and chronic stress, confirming the remarkable plasticity of CA3 dendrites. They provide a clear illustration of the structural modifications that occur after life experiences noted for their different impact on hippocampal function.

Stress Effects on Working Memory, Explicit Memory, and Implicit Memory for Neutral and Emotional Stimuli in Healthy Men

Stress is a strong modulator of memory function. However, memory is not a unitary process and stress seems to exert different effects depending on the memory type under study. Here, we explored the impact of social stress on different aspects of human memory, including tests for explicit memory and working memory (for neutral materials), as well as implicit memory (perceptual priming, contextual priming and classical conditioning for emotional stimuli). A total of 35 young adult male students were randomly assigned to either the stress or the control group, with stress being induced by the Trier Social Stress Test (TSST). Salivary cortisol levels were assessed repeatedly throughout the experiment to validate stress effects. The results support previous evidence indicating complex effects of stress on different types of memory: A pronounced working memory deficit was associated with exposure to stress. No performance differences between groups of stressed and unstressed subjects were observed in verbal explicit memory (but note that learning and recall took place within 1 h and immediately following stress) or in implicit memory for neutral stimuli. Stress enhanced classical conditioning for negative but not positive stimuli. In addition, stress improved spatial explicit memory. These results reinforce the view that acute stress can be highly disruptive for working memory processing. They provide new evidence for the facilitating effects of stress on implicit memory for negative emotional materials. Our findings are discussed with respect to their potential relevance for psychiatric disorders, such as post traumatic stress disorder.

Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training.

The impact was examined of exposing rats to two life experiences of a very different nature (stress and learning) on synaptic structures in hippocampal area CA3. Rats were subjected to either (i) chronic restraint stress for 21 days, and/or (ii) spatial training in a Morris water maze. At the behavioural level, restraint stress induced an impairment of acquisition of the spatial response. Moreover, restraint stress and water maze training had contrasting impacts on CA3 synaptic morphometry. Chronic stress induced a loss of simple asymmetric synapses [those with an unperforated postsynaptic density (PSD)], whilst water maze learning reversed this effect, promoting a rapid recovery of stress‐induced synaptic loss within 2–3 days following stress. In addition, in unstressed animals a correlation was found between learning efficiency and the density of synapses with an unperforated PSD: the better the performance in the water maze, the lower the synaptic density. Water maze training increased the number of perforated synapses (those with a segmented PSD) in CA3, both in stressed and, more notably, in unstressed rats. The distinct effects of stress and learning on CA3 synapses reported here provide a neuroanatomical basis for the reported divergent effects of these experiences on hippocampal synaptic activity, i.e. stress as a suppressor and learning as a promoter of synaptic plasticity.