Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory.

Different pathological tau species are involved in memory loss in Alzheimer’s disease, the most common cause of dementia among older people. However, little is known about how tau pathology directly affects adult hippocampal neurogenesis, a unique form of structural plasticity implicated in hippocampusdependent spatial learning and mood-related behavior. To this aim, we generated a transgenic mouse model conditionally expressing a pathological tau fragment (26e230 aa of the longest human tau isoform, or N-tau) in nestin-positive stem/progenitor cells. We found that N-tau reduced the proliferation of progenitor cells in the adult dentate gyrus, reduced cell survival and increased cell death by a caspase- 3eindependent mechanism, and recruited microglia. Although the number of terminally differentiated neurons was reduced, these showed an increased dendritic arborization and spine density. This resulted in an increase of anxiety-related behavior and an impairment of episodic-like memory, whereas less complex forms of spatial learning remained unaltered. Understanding how pathological tau species directly affect neurogenesis is important for developing potential therapeutic strategies to direct neurogenic instructive cues for hippocampal function repair

Food restriction reduces neurogenesis in the avian hippocampal formation

The mammalian hippocampus is particularly vulnerable to chronic stress. Adult neurogenesis in the dentate gyrus is suppressed by chronic stress and by administration of glucocorticoid hormones. Post-natal and adult neurogenesis are present in the avian hippocampal formation as well, but much less is known about its sensitivity to chronic stressors. In this study, we investigate this question in a commercial bird model: the broiler breeder chicken. Commercial broiler breeders are food restricted during development to manipulate their growth curve and to avoid negative health outcomes, including obesity and poor reproductive performance. Beyond knowing that these chickens are healthier than fully-fed birds and that they have a high motivation to eat, little is known about how food restriction impacts the animals' physiology. Chickens were kept on a commercial food-restricted diet during the first 12 weeks of life, or released from this restriction by feeding them ad libitum from weeks 7-12 of life. To test the hypothesis that chronic food restriction decreases the production of new neurons (neurogenesis) in the hippocampal formation, the cell proliferation marker bromodeoxyuridine was injected one week prior to tissue collection. Corticosterone levels in blood plasma were elevated during food restriction, even though molecular markers of hypothalamic-pituitary-adrenal axis activation did not differ between the treatments. The density of new hippocampal neurons was significantly reduced in the food-restricted condition, as compared to chickens fed ad libitum, similar to findings in rats at a similar developmental stage. Food restriction did not affect hippocampal volume or the total number of neurons. These findings indicate that in birds, like in mammals, reduction in hippocampal neurogenesis is associated with chronically elevated corticosterone levels, and therefore potentially with chronic stress in general. This finding is consistent with the hypothesis that the response to stressors in the avian hippocampal formation is homologous to that of the mammalian hippocampus

Extinction after retrieval: Effects on the associative and nonassociative components of remote contextual fear memory

Long-lasting memories of adverse experiences are essential for individuals' survival but are also involved, in the form of recurrent recollections of the traumatic experience, in the aetiology of anxiety diseases (e. g., post-traumatic stress disorder [PTSD]). Extinction-based erasure of fear memories has long been pursued as a behavioral way to treat anxiety disorders; yet, such a procedure turns out to be transient, context-dependent, and ineffective unless it is applied immediately after trauma. Recent evidence indicates that, in both rats and humans, extinction training can prevent the return of fear if administered within the reconsolidation window, when memories become temporarily labile and susceptible of being updated. Here, we show that the reconsolidation-extinction procedure fails to prevent the spontaneous recovery of a remote contextual fear memory in a mouse model of PTSD, as well as the long-lasting behavioral abnormalities induced by traumatic experience on anxiety and in both social and cognitive domains (i.e., social withdrawal and spatial learning deficits). Such a failure appears to be related to the ineffectiveness of the reconsolidation-extinction procedure in targeting the pathogenic process of fear sensitization, a nonassociative component of traumatic memory that causes animals to react aberrantly to harmless stimuli. This indicates fear sensitization as a major target for treatments aimed at mitigating anxiety and the behavioral outcomes of traumatic experiences

RISC activity in hippocampus is essential for contextual memory

RNA-Induced Silencing Complex (RISC) mediates post-transcriptional control of gene expression and contains Argonaute 2 (AGO2) protein as a central effector of cleavage or inhibition of mRNA translation. In the brain, the RISC pathway is involved in neuronal functions, such as synaptic development and local protein synthesis, which are potentially critical for memory. In this study, we examined the role of RISC in memory formation in rodents, by silencing AGO2 expression in dorsal hippocampus of C57BL/6 mice and submitting animals to hippocampus-related tasks. One week after surgery, AGO2 downregulation impaired both short-term and long-term contextual fear memories. Conversely, no long-lasting effects were observed three weeks after surgery, when AGO2 levels were re-established. These results show that altered RISC activity severely affects learning and memory processes in rodents

MEMORY IMPAIRMENT INDUCED BY AN INTERFERING TASK IS REVERTED BY PRE-FRONTAL CORTEX LESIONS: A POSSIBLE ROLE FOR AN INHIBITORY PROCESS IN MEMORY SUPPRESSION IN MICE

Interference theory refers to the idea that forgetting occurs because the recall of certain items interferes with the recall of other items. Recently, it has been proposed that interference is due to an inhibitory control mechanism, triggered by competing memories, that ultimately causes forgetting [Anderson MC (2003) Rethinking interference theory: Executive control and the mechanisms of forgetting. J Mem Lang 49:415-4453]. In the present research we study the interference process by submitting CD1 mice to two different hippocampal-dependent tasks: a place object recognition task (PORT) and a step-through inhibitory avoidance task (IA). Our results show a mutual interference between PORT and IA. To elucidate the possible neural mechanism underlying the interference process, we submit hippocampus- and prefrontal cortex-lesioned mice to PORT immediately before IA training. Results from these experiments show that prefrontal cortex lesions completely revert the impairing effect exerted by PORT administration on IA memory, while hippocampus lesions, that as expected impair memory for both PORT and IA, increase this effect. Altogether our results suggest that interference-induced forgetting is driven by an inhibitory control mechanism through activation of hippocampus-prefrontal cortex circuitry. The hippocampus seems to be crucial for storing information related to both behavioral tasks. Competition between memories triggers the inhibitory control mechanism, by activating prefrontal cortex, and induces memory suppression. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved

Fear but not fright: re-evaluating traumatic experience attenuates anxiety-like behaviors after fear conditioning.

Fear allows organisms to cope with dangerous situations and remembering these situations has an adaptive role preserving individuals from injury and death. However, recalling traumatic memories can induce re-experiencing the trauma, thus resulting in a maladaptive fear. A failure to properly regulate fear responses has been associated with anxiety disorders, like Posttraumatic Stress Disorder (PTSD). Thus, re-establishing the capability to regulate fear has an important role for its adaptive and clinical relevance. Strategies aimed at erasing fear memories have been proposed, although there are limits about their efficiency in treating anxiety disorders. To re-establish fear regulation, here we propose a new approach, based on the re-evaluation of the aversive value of traumatic experience. Mice were submitted to a contextual-fear-conditioning paradigm in which a neutral context was paired with an intense electric footshock. Three weeks after acquisition, conditioned mice were treated with a less intense footshock (pain threshold). The effectiveness of this procedure in reducing fear expression was assessed in terms of behavioral outcomes related to PTSD (e.g., hyper-reactivity to a neutral tone, anxiety levels in a plus maze task, social avoidance, and learning deficits in a spatial water maze) and of amygdala activity by evaluating c-fos expression. Furthermore, a possible role of lateral orbitofrontal cortex (lOFC) in mediating the behavioral effects induced by the re-evaluation procedure was investigated. We observed that this treatment: (i) significantly mitigates the abnormal behavioral outcomes induced by trauma; (ii) persistently attenuates fear expression without erasing contextual memory; (iii) prevents fear reinstatement; (iv) reduces amygdala activity; and (v) requires an intact lOFC to be effective. These results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of the traumatic experience mediated by lOFC

The effect of emotional valence and arousal on visuo-spatial working memory: incidental emotional learning and memory for object-location

Remembering places in which emotional events occur is essential for individual’s survival. However, the mechanisms through which emotions modulate information processing in working memory, especially in the visuo-spatial domain, is little understood and controversial. The present research was aimed at investigating the effect of incidentally learned emotional stimuli on visuo-spatial working memory (VSWM) performance by using a modified version of the object-location task. Eight black rectangles appeared simultaneously on a computer screen; this was immediately followed by the sequential presentation of eight pictures (selected from IAPS) superimposed onto each rectangle. Pictures were selected considering the two main dimensions of emotions: valence and arousal. Immediately after presentation, participants had to relocate the rectangles in the original position as accurately as possible. In the first experiment arousal and valence were manipulated either as between-subject (Experiment 1A) or as within-subject factors (Experiment 1B and 1C). Results showed that negative pictures enhanced memory for object location only when they were presented with neutral ones within the same encoding trial. This enhancing effect of emotion on memory for object location was replicated also with positive pictures. In Experiment 2 the arousal level of negative pictures was manipulated between-subjects (high vs. low) while maintaining valence as a within-subject factor (negative vs. neutral). Objects associated with negative pictures were better relocated, independently of arousal. In Experiment 3 the role of emotional valence was further ascertained by manipulating valence as a within-subject factor (neutral vs. negative in Experiment 3A; neutral vs. positive in Experiment 3B) and maintaining similar levels of arousal among pictures. A significant effect of valence on memory for location was observed in both experiments. Finally, in Experiment 4, when positive and negative pictures were encoded in the same trial, no significant effect of valence on memory for object location was observed. Taken together results suggest that emotions enhance spatial memory performance when neutral and emotional stimuli compete with one another for access into the working memory system. In this competitive mechanism, an interplay between valence and arousal seems to be at work

The attentional boost effect enhances the recognition of bound features in short-term memory

In the Attentional Boost Effect (ABE), images or words encoded with unrelated to-be-responded targets are later remembered better than images or words encoded with to-be-ignored distractors. In the realm of short-term memory, the ABE has been previously shown to enhance the short-term recognition of single-feature stimuli. The present study replicated this finding and extended it to a condition requiring the encoding and retention of colour-shape associations. Across four experiments, participants studied arrays of four coloured squares (the colour-only condition), four gray shapes (the shape-only condition) or four coloured shapes (the binding condition), paired with either a target letter (to which participants had to respond by pressing the spacebar) or a distractor letter (for which no response was required). After a short delay, they were presented with a probe array and asked to decide whether it matched or not the encoded array. Results showed that, in all conditions, the recognition of target-paired arrays was significantly better than the recognition of distractor-paired arrays. These findings suggest that the ABE can enhance feature binding