Véronique Paban

Age-related changes in metabolic profiles of rat hippocampus and cortices

The time course of metabolic changes was investigated in the hippocampus and the parietal, rhinal and frontal cortices of rats from 4 to 30 months old. Samples were analysed by the solid‐state high‐resolution magic angle spinning nuclear magnetic resonance method. Quantification was performed with the quest procedure of jmrui software. Eighteen metabolites were identified and separated in the spectrum. Six of them were not age sensitive, in particular alanine, glutamine and lactate. In contrast, choline, glycerophosphocholine, myo‐inositol, N‐acetylaspartate, scyllo‐inositol (s‐Ins) and taurine (Tau) were notably altered over aging. Interestingly, each age group showed a specific metabolic profile. The concentration of metabolites such as Tau was altered in middle‐aged rats only, whereas the s‐Ins level decreased in old rats only. Most metabolites showed progressive alteration during the process of aging, which was initiated during the middle‐aged period (18 months). Taken together, these results suggest that cell membrane integrity is perturbed with age. Each brain region investigated had distinctive qualitative and/or quantitative metabolic age‐related features. These age‐related changes would affect network connectivities and then cognitive functions.

Neurotrophic signaling molecules associated with cholinergic damage in young and aged rats: Environmental enrichment as potential therapeutic agent

The aim of this study was to determine the neurobiological bases of behavioral deficits associated with cholinergic damage and the potential of long-term environmental enrichment as a therapeutic agent. Rats were submitted to intra-structures injection of 192 IgG-saporin and then behaviorally tested 1 month and 1 year post-lesion in a nonmatching-to-position task. The gene expression changes were assessed by cDNA macroarray technology using the GE array Q series designed to profile the expression of neurotrophic signaling molecules. Results showed that (1) cholinergic injury modulated the expression of genes such as brain-derived neurotrophin factor but also genes associated with inflammatory response, neuron apoptosis, regulation of angiogenesis, and synaptic plasticity, (2) aging is associated with regulation of glial proliferation and apoptosis, and (3) long-term enriched environment housing enhanced behavioral performance in lesioned and non-lesioned rats and upregulated gene expression. This therapeutic role of the enriched environment seemed to be associated with a suppression of expression of genes involved in apoptosis, glial cell differentiation, and cell cycle, but also with an enhanced expression of a subset of genes involved in signal transduction.

Behavioral Effects of Basal Forebrain Cholinergic Lesions in Young Adult and Aging Rats

The interactive effects of age and cholinergic damage were assessed behaviorally in young and middle-aged rats. Rats were lesioned at either 3 or 17 months of age by injection of 192 IgG-saporin immunotoxin into the medial septum and the nucleus basalis magnocellularis, and they were then tested on a range of behavioral tasks: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. Depending on the task used, only an age or a lesion effect was observed, but there was no Age X Lesion interaction. Middle-aged and young rats responded to the cholinergic lesions in the same manner. These results show that in the middle-aged rats in which cholinergic transmission was affected, additional injury to the system was not always accompanied by major cognitive dysfunctions.

Fos protein expression induced by intracerebroventricular injection of vasopressin in unconditioned and conditioned mice.

Arginine8-vasopressin (AVP) has been shown to improve memory consolidation in various mnemonic tasks. Our previous studies have pointed out the involvement of the hippocampus in memory consolidation and retrieval processes during discriminative learning by mice. The present study attempts to determine what other brain areas besides the hippocampus might be involved in the enhancing effect of intracerebroventricularly (i.c.v.) injected AVP on memory consolidation in a visual discrimination task using a polyclonal antibody that acts against Fos and Fos-like proteins. For behavioral testing, AVP was i.c.v. injected at the behaviorally active dose of 2 ng after the last learning session and improvement in consolidation processes was assessed in a retention session. Changes in Fos and Fos-like protein expression were determined in non-conditioned and conditioned mice. In non-conditioned mice, AVP i. c.v. injected at a dose of 2 ng evoked a time-dependent increase in Fos and Fos-like protein expression in the dentate gyrus (DG), CA1 and CA3 hippocampal fields, lateral septum (LS), bed nucleus of the stria terminalis, and basolateral and central amygdaloid nuclei, with a peak 120 min after the injection in most of the these brain areas. In contrast, in conditioned mice, an increase in the level of Fos expression, assessed 120 min after the end of learning and the injection of AVP, was detected only in the DG, ventral CA3 hippocampal field, and LS. Thus, the pattern observed after post-training injection of AVP was not the same as that evoked by AVP alone, since among the limbic structures activated following AVP alone, only the DG, the CA3 hippocampal field, and the LS seem to be involved in the enhancing effect of AVP on memory consolidation in discriminative learning.

Behavioral effects of arginine8-vasopressin in the Hebb–Williams maze

Arginine(8)-vasopressin (AVP) has been shown to improve memory consolidation in various mnemonic tasks. Our previous studies have pointed out the involvement of the hippocampus (with higher sensitivity of its ventral part) in memory consolidation and retrieval processes during discriminative learning in mice. The present study was designed to extend our knowledge, firstly, of the range of tasks and consequently the types of information for which the peptide improves consolidation processes, and secondly, the effects of AVP on information treatment processes such an information transfer. To this end, the effects of AVP were analyzed in the Hebb-Williams closed-field maze. Mice were initially trained on one of the mazes in the Hebb-Williams series (Maze 7) and subsequently tested on either that maze or another maze in the series (Maze 11). The effects of the peptide on both memory consolidation and information transfer processes were analyzed in relation to the route of administration: peripheral (subcutaneous, s.c.), central (intracerebroventricular, i.c.v.), and in situ (dorsal or ventral hippocampus). The results showed that AVP facilitated spatial memory consolidation following s.c., i.c.v, and dorsal, but not ventral hippocampal administration. This differential effect of AVP following injection into the hippocampus can be interpreted in regards to this structures functions. In line with the involvement of the dorsal hippocampus in spatial memory, the effectiveness of the peptide in the Hebb-Williams maze, which contains spatial components, was better when the treatment was performed in this part of the structure. In contrast, whatever the route of administration, AVP had no effect on processes related to the transfer from one learning situation to another.

Benefits of Computer-Based Memory and Attention Training in Healthy Older Adults

Multifactorial cognitive training programs have a positive effect on cognition in healthy older adults. Among the age-sensitive cognitive domains, episodic memory is the most affected. In the present study, we evaluated the benefits on episodic memory of a computer-based memory and attention training. We targeted consciously controlled processes at encoding and minimizing processing at retrieval, by using more familiarity than recollection during recognition. Such an approach emphasizes processing at encoding and prevents subjects from reinforcing their own errors. Results showed that the training improved recognition performances and induced near transfer to recall. The largest benefits, however, were for tasks with high mental load. Improvement in free recall depended on the modality to recall; semantic recall was improved but not spatial recall. In addition, a far transfer was also observed with better memory self-perception and self-esteem of the participants. Finally, at 6-month follow up, maintenance of benefits was observed only for semantic free recall. The challenge now is to corroborate far transfer by objective measures of everyday life executive functioning.

Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: alteration of c-Fos and polysialylated neural cell adhesion molecule expression.

The aim of this study was to determine the brain structures as well as the plasticity events associated with the behavioral effects of cholinergic damage. Rats were submitted to injection of 192 IgG-saporin in the medial septum/diagonal band of Broca complex and the nucleus basalis magnocellularis. The immunohistochemical expression of c-Fos protein and PSA-NCAM (polysialylated neural cell adhesion molecule) and the behavioral performances in the nonmatching-to-position task were assessed at various post-lesion times. Thus, 3 days after injection of the immunotoxin, increased c-Fos labeling was observed in the areas of infusion, indicating these cells were undergoing some plastic changes and/or apoptotic processes. A drastic increase was observed in the number of PSA-NCAM positive cells and in their dendritic arborization in the dentate gyrus. At 7 days post-lesion, no behavioral deficit was observed in immunolesioned rats despite the drastic loss of cholinergic neurons. These neurons showed decreased c-Fos protein expression in the piriform and entorhinal cortex and in the dentate gyrus. In the latter, PSA-NCAM induction was high, suggesting that remodeling occurred, which in turn might contribute to sustaining some mnemonic function in immunolesioned rats. At 1 month, cholinergic neurons totally disappeared and behavioral deficits were drastic. c-Fos expression showed no change. In contrast, the increased PSA-NCAM-labeling observed at short post-lesion times was maintained but the plastic changes due to this molecule could not compensate the behavioral deficit caused by the immunotoxin. Thus, as the post-lesion time increases, a gradual degeneration process should occur that may contribute to mnemonic impairments. This neuronal loss leads to molecular and cellular alterations, which in turn may aggravate cognitive deficits.

Gene expression profile in rat hippocampus with and without memory deficit

The cholinergic neuronal system, through its projections to the hippocampus, plays an important role in learning and memory. The aim of the study was to identify genes and networks in rat hippocampus with and without memory deficit. Genome-scale screening was used to analyze gene expression changes in rats submitted or not to intraparenchymal injection of 192 IgG-saporin and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes that could be grouped into several clusters of similar expression profiles and that are involved in biological functions, namely lipid metabolism, signal transduction, protein metabolism and modification, and transcription regulation. Memory loss following hippocampal cholinergic deafferentation was associated with significant expression of genes that did not show similar cluster organization. Only one cluster of genes could be identified; it included genes that would be involved in tissue remodeling. More important, most of the genes significantly altered in lesioned rats were down-regulated.

Gene regulation in the rat prefrontal cortex after learning with or without cholinergic insult.

The prefrontal cortex is essential for a wide variety of higher functions, including attention and memory. Cholinergic neurons are thought to be of prime importance in the modulation of these processes. Degeneration of forebrain cholinergic neurons has been linked to several neurological disorders. The present study was designed to identify genes and networks in rat prefrontal cortex that are associated with learning and cholinergic-loss-memory deficit. Affymetrix microarray technology was used to screen gene expression changes in rats submitted or not to 192 IgG-saporin immunolesion of cholinergic basal forebrain and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes, which were organized in several clusters of highly correlated genes and would be involved in biological processes such as intracellular signaling process, transcription regulation, and filament organization and axon guidance. Memory loss following cortical cholinergic deafferentation was associated with significant expression of genes belonging to only one clearly delineated cluster and would be involved in biological processes related to cytoskeleton organization and proliferation, and glial and vascular remodeling, i.e., in processes associated with brain repair after injury.

Molecular gene expression following blunt and rotational models of traumatic brain injury parallel injuries associated with stroke and depression

Traumatic brain injury (TBI) is associated with a collection of physical, emotional and cognitive post complications. The background for such complex consequences may be due to a number of different factors, and the nature of these changes indicates that the frontal lobes may be implicated. In this study we have employed gene expression arrays and gene ontology databases to search for possible similarities between different forms of acquired brain injuries in order to test whether molecular relationships exist between the different pathologies. Two types of experimental models for traumatic brain injuries, lateral fluid percussion and rotational acceleration, were used. Their molecular signature was identified and compared with those related to other rodent models simulating stress, depression, alcohol dependence, stroke, and Alzheimer’s disease. The data show that the two TBI models share similar gene expression changes with the models with regard to depression and stroke, indicating a common molecular support between these pathologies. The data provided can contribute to the introduction of new treatment strategies related to TBI.