Reduced impact of emotion on choice behavior in presymptomatic BACHD rats, a transgenic rodent model for Huntington Disease.

Executive dysfunction and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder genetically characterized by expanded CAG repeats in the HTT gene. Using the BACHD rat model of HD (97 CAG-CAA repeats), the present research seeks to characterize the progressive emergence of decision-making impairments in a rat version of the Iowa Gambling Task (RGT) and the impact of emotional modulation, whether positive or negative, on choice behavior. The choice efficiency shown both by WT rats (independent of their age) and the youngest BACHD rats (2 and 8months old) evidenced that they are able to integrate outcomes of past decisions to determine expected reward values for each option. However, 18months old BACHD rats made fewer choices during the RGT session and were less efficient in choosing advantageous options than younger animals. Presenting either chocolate pellets or electrical footshocks half-way through a second RGT session reduced exploratory activity (inefficient nose-poking) and choices with a weaker effect on BACHD animals than on WT. Choice efficiency was left intact in transgenic rats. Our results bring new knowledge on executive impairments and impact of emotional state on decision-making at different stages of the disease, increasing the face-validity of the BACHD rat model.

A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval.

Recent research has revived interest in the possibility that previously consolidated memories need to reconsolidate when recalled to return to accessible long-term memory. Evidence suggests that both consolidation and reconsolidation of certain types of memory require protein synthesis, but whether similar molecular mechanisms are involved remains unclear. Here, we explore whether zif268, an activity-dependent inducible immediate early gene (IEG) required for consolidation of new memories, is also recruited for reconsolidation of recognition memory following reactivation. We show that when a consolidated memory for objects is recalled, zif268 mutant mice are impaired in further long-term but not short-term recognition memory. The impairment is specific to reactivation with the previously memorized objects in the relevant context, occurs in delayed recall, and does not recover over several days. These findings indicate that IEG-mediated transcriptional regulation in neurons is one common molecular mechanism for the storage of newly formed and reactivated recognition memories.

Altered social behavior and ultrasonic communication in the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy.

BACKGROUND: The Duchenne and Becker muscular dystrophies (DMD, BMD) show significant comorbid diagnosis for autism, and the genomic sequences encoding the proteins responsible for these diseases, the dystrophin and associated proteins, have been proposed as new candidate risk loci for autism. Dystrophin is expressed not only in muscles but also in central inhibitory synapses in the cerebellum, hippocampus, amygdala, and cerebral cortex, where it contributes to the organization of autism-associated trans-synaptic neurexin-neuroligin complexes and to the clustering of synaptic gamma-aminobutyric acid (GABA)A receptors. While brain defects due to dystrophin loss are associated with deficits in cognitive and executive functions, communication skills and social behavior, only a subpopulation of DMD patients meet the criteria for autism, suggesting that mutations in the dystrophin gene may confer a vulnerability to autism. The loss of dystrophin in the mdx mouse model of DMD has been associated with cognitive and emotional alterations, but social behavior and communication abilities have never been studied in this model. METHODS: Here, we carried out the first in-depth analysis of social behavior and ultrasonic communication in dystrophin-deficient mdx mice, using a range of socially relevant paradigms involving various degrees of executive and cognitive demands, from simple presentation of sexual olfactory stimuli to social choice situations and direct encounters with female and male mice of various genotypes. RESULTS: We identified context-specific alterations in social behavior and ultrasonic vocal communication in mdx mice during direct encounters in novel environments. Social behavior disturbances depended on intruders' genotype and behavior, suggesting alterations in executive functions and adaptive behaviors, and were associated with selective alterations of the development, rate, acoustic properties, and use of the ultrasonic vocal repertoire. CONCLUSIONS: This first evidence that a mutation impeding expression of brain dystrophin affects social behavior and communication sheds new light on critical cognitive, emotional, and conative factors contributing to the development of autistic-like traits in this disease model.

How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning?

The immediate early genes (IEGs) are activated rapidly and transiently in response to a multitude of stimuli. The zif268 belongs to a category of regulatory IEGs that activate downstream target genes and is considered to be a triggering mechanism to activate the genomic response in neurons. Several studies have shown that zif268 mRNA is upregulated during different forms of associative learning, and following tetanic stimulation that induces long-lasting LTP. To date, there is a general consensus that zif268 activation may constitute a critical mechanism for the encoding of long-lasting memories, however this is based on relatively few studies. Given the fact that zif268 can be activated by a number of different types of stimuli, it becomes important to determine exactly how it may be implicated in memory. Examination of the current literature suggests that zif268 is necessary in the processing of several types of memory, however, it is not entirely clear what aspects of memory zif268 may be implicated in. Here, we review the existing literature and emphasise that understanding the signalling pathways that lead to activation of the IEGs and the downstream targets of these genes will advance our understanding of how functional activation of zif268 may be implicated in processing long-term memories.

Modified impact of emotion on temporal discrimination in a transgenic rat model of Huntington disease.

Huntington's disease (HD) is characterized by triad of motor, cognitive, and emotional symptoms along with neuropathology in fronto-striatal circuit and limbic system including amygdala. Emotional alterations, which have a negative impact on patient well-being, represent some of the earliest symptoms of HD and might be related to the onset of the neurodegenerative process. In the transgenic rat model (tgHD rats), evidence suggest emotional alterations at the symptomatic stage along with neuropathology of the central nucleus of amygdala (CE). Studies in humans and animals demonstrate that emotion can modulate time perception. The impact of emotion on time perception has never been tested in HD, nor is it known if that impact could be part of the presymptomatic emotional phenotype of the pathology. The aim of this paper was to characterize the effect of emotion on temporal discrimination in presymptomatic tgHD animals. In the first experiment, we characterized the acute effect of an emotion (fear) conditioned stimulus on temporal discrimination using a bisection procedure, and tested its dependency upon an intact central amygdala. The second experiment was aimed at comparing presymptomatic homozygous transgenic animals at 7-months of age and their wild-type littermates (WT) in their performance on the modulation of temporal discrimination by emotion. Our principal findings show that (1) a fear cue produces a short-lived decrease of temporal precision after its termination, and (2) animals with medial CE lesion and presymptomatic tgHD animals demonstrate an alteration of this emotion-evoked temporal distortion. The results contribute to our knowledge about the presymptomatic phenotype of this HD rat model, showing susceptibility to emotion that may be related to dysfunction of the central nucleus of amygdala.

A standardized method to automatically segment amyloid plaques in Congo Red stained sections from Alzheimer transgenic mice.

Automated detection of amyloid plaques (AP) in post mortem brain sections of patients with Alzheimer disease (AD) or in mouse models of the disease is a major issue to improve quantitative, standardized and accurate assessment of neuropathological lesions as well as of their modulation by treatment. We propose a new segmentation method to automatically detect amyloid plaques in Congo Red stained sections based on adaptive thresholds and a dedicated amyloid plaque/tissue modelling. A set of histological sections focusing on anatomical structures was used to validate the method in comparison to expert segmentation.

Fully automated and adaptive detection of amyloid plaques in stained brain sections of Alzheimer transgenic mice.

Automated detection of amyloid plaques (AP) in post mortem brain sections of patients with Alzheimer disease (AD) or in mouse models of the disease is a major issue to improve quantitative, standardized and accurate assessment of neuropathological lesions as well as of their modulation by treatment. We propose a new segmentation method to automatically detect amyloid plaques in Congo Red stained sections based on adaptive thresholds and a dedicated amyloid plaque/tissue modelling. A set of histological sections focusing on anatomical structures was used to validate the method in comparison to expert segmentation. Original information concerning global amyloid load have been derived from 6 mouse brains which opens new perspectives for the extensive analysis of such a data in 3-D and the possibility to integrate in vivo-post mortem information for diagnosis purposes.

Regulated transcription of the immediate-early gene Zif268: mechanisms and gene dosage-dependent function in synaptic plasticity and memory formation.

The immediate-early gene Zif268 is a member of the Egr family of inducible transcription factors. Data from gene expression studies have suggested that this gene may play a critical role in initial triggering of the genetic machinery that has long been considered a necessary mechanism for maintenance of the later phases of LTP and also for the consolidation or stabilization of long-lasting memories. Until recently, however, the data supporting this assumption have been based primarily on circumstantial evidence, with no direct evidence to suggest that Zif268 is required for long-lasting synaptic plasticity and memory. In this report, we review our own data using Zif268 mutant mice; we show that although the early phase of dentate gyrus LTP is normal in these mice, the later phases are not present, and the ability of the mice to maintain learned information over a 24-h period is deficient. In addition, we present new information showing a task-dependent gene dosage effect in Zif268 heterozygous mice. We show that spatial learning is particularly sensitive to reduced levels of Zif268, as one-half of the complement of Zif268 in heterozygous mice is insufficient to maintain spatial long-term memories.

MAPK, CREB and zif268 are all required for the consolidation of recognition memory.

There has been nearly a century of interest in the idea that encoding and storage of information in the brain requires changes in the efficacy of synaptic connections between neurons that are activated during learning. Recent research into the molecular mechanisms of long-term potentiation (LTP) has brought about new knowledge that has provided valuable insights into the neural mechanisms of memory storage. The evidence indicates that rapid activation of the genetic machinery can be a key mechanism underlying the enduring modification of neural networks required for the stability of memories. In recent years, a wealth of experimental data has highlighted the importance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling in the regulation of gene transcription in neurons. Here, we briefly review experiments that have shown MAPK/ERK, cAMP response element-binding protein (CREB) and the immediate early gene (IEG) zif268 are essential components of a signalling cascade required for the expression of late phase LTP and of certain forms of long-term memory. We also present experiments in which we have assessed the role of these three molecules in recognition memory. We show that pharmacological blockade of MAPK/ERK phosphorylation, functional inactivation of CREB in an inducible transgenic mouse and inactivation of zif268 in a mutant mouse result in a similar deficit in long-term recognition memory. In the continuing debate about the role of LTP mechanisms in memory, these findings provide an important complement to the suggestion that synaptic changes brought about by LTP and memory consolidation and storage share, at least in part, common underlying molecular mechanisms.