Béatrice Alescio-Lautier

Time course of behavioral changes following basal forebrain cholinergic damage in rats: Environmental enrichment as a therapeutic intervention

The present experiment was designed to study changes in behavior following immunolesioning of the basal forebrain cholinergic system. Rats were lesioned at 3 months of age by injection of the 192 IgG-saporin immunotoxin into the medial septum area and the nucleus basalis magnocellularis, and then tested at different times after surgery (from days 7-500) on a range of behavioral tests, administered in the following order: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. The results revealed a two-way interaction between post-lesion behavioral testing time and memory demands. In the nonmatching-to-position task, memory deficits appeared quite rapidly after surgery, i.e. at a post-lesion time as short as 1 month. In the object-recognition test, memory impairments appeared only when rats were tested at late post-lesion times (starting at 15 months), whereas in the object-location task deficits were apparent at early post-lesion times (starting from 2 months). Taking the post-operative time into account, one can hypothesize that at the shortest post-lesion times, behavioral deficits are due to pure cholinergic depletion, while as the post-lesion time increases, one can speculate the occurrence of a non-cholinergic system decompensation process and/or a gradual degeneration process affecting other neuronal systems that may contribute to mnemonic impairments. Interestingly, when middle-aged rats were housed in an enriched environment, 192 IgG-saporin-lesioned rats performed better than standard-lesioned rats on both the nonmatching-to-position and the object-recognition tests. Environment enrichment had significant beneficial effects in 192 IgG-saporin-lesioned rats, suggesting that lesioned rats at late post-lesion times (over 1 year) still have appreciable cognitive plasticity.

Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer's disease

According to one of the theories formulated to explain the etiology of Alzheimers disease (AD), amylosis may reflect a specific inflammatory response. Two inflammatory proteins, lithostathine and PAP, were evidenced by immunohistochemistry in senile plaques and neurofibrillary tangles of patients with AD. In addition, lithostathine and PAP were significantly increased in the cerebrospinal fluid of patients with AD when compared to patients with multiple sclerosis, another inflammatory disease, and to normal control subjects. However, no correlation was observed with age of occurrence. Furthermore, lithostathine and PAP were increased even at the very early stages of AD, and their level remained elevated during the course of the AD unlike TNFalpha whose level, very high at very early stages, regularly decreased. Finally, if part of lithostathine and PAP are synthesized in the brain, a large part comes from serum by passage over the blood-brain barrier. These results indicate (i) the existence of an acute phase response followed by a chronic inflammation in AD, and (ii) that lithostathine and PAP are involved even at the first pre-clinical biochemical events of AD. In addition, because lithostathine undergoes an autolytic cleavage leading to its precipitation and the formation of fibrils, we believe that it may be involved in amyloidosis and tangles by allowing heterogeneous precipitation of other proteins.

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.

Central behavioral effects of vasopressin: point and perspectives.

It is now an established fact that for a variety of species, neuropeptides play an important role in the control and expression of certain behavior. Examples are found in rodents, in which drinking is activated by angiotensin II, maternal behavior is accelerated by oxytocin, feeding is inhibited by bombesin and cholecystokinin, stereotyped grooming is induced by ACTH, and lordotic behavior is inhibited by vasopressin. Some of these neuropeptides, such as ACTH and vasopressin, can induce behavioral changes which result from the action of more complex processes than those at play in the behaviors mentioned above. These processes are the ones involved in learned behaviors. In this case, these neuropeptides not only contribute to the control and expression of pre-programmed physiological behaviors, but are also involved in the acquisition and retention of new behaviors. In other words, certain neuropeptides are assumed to act in learning and retention processes, although the nature of their action is not yet known. Indeed, a process as complex as memory results from the interaction of numerous factors including the subjects motivational, emotional, and arousal states, which can directly or indirectly act upon the neural support of memory processes. Moreover, the nature of the information conveyed in these neural circuits depends on the interaction of certain molecules and/or on their neuromodulation. This makes it difficult to determine whether neuropeptides affect learning, memory consolidation and retention: (i) by activating the emotional and arousal states which produced the optimal conditions for learning, memory storage and retrieval; (ii) by acting directly upon the neural circuit involved in these memory processes, or (iii) by a combination of the two. Following the pioneering work by De Wied nearly twenty years ago, many studies have shown that arginine-vasopressin (AVP) affects many behaviors, especially learned ones. AVP is a posthypophysial nonapeptide known to be an antidiuretic and pressor hormone. Its biosynthesis /121,130,135,136/ takes place mainly in the supraoptic and paraventricular nuclei of the hypothalamus /139/. It is secreted and stored in the posterior hypophysis. From there, it is released into the systemic circulation in response to Cadependent action potentials /147/. The magnocellular vasopressinergic neurons of the hypothalamic nuclei and their projections to the neurohypophysis constitute the main component of the classic endocrine hypothalamusneurohypophysial pathway /119/. The pressor and antidiuretic activities of AVP are currently well known /43,151/ and its endocrine effects are mediated through receptors on target organs, including VI receptors on smooth muscle cells lining blood vessels associated with the pressor response /125/, and V2 receptors in the kidney which are essential for the renal antidiuretic actions of AVP /39/. It gradually became known that in addition to the fibers originating in the hypothalamic nuclei which make up the hypothalamus-neurohypophysial pathway, there are also vasopressinergic fibers in numerous cerebral regions in the guinea-pig 1621, rat /30,141/, and mouse /42/, ranging from the olfactory bulb to the spinal cord, in addition to vasopressinergic neuron groups in the septal region /140/, the bed nucleus of the stria terminalis, the medial amygdaloid nucleus, and the locus coeruleus /51,140/. These vasopressinergic pathways, called extrahypothalamic pathways, are shown in Figure 1, in which we can see that the projections of certain vasopressinergic neuron groups and the origins of certain vasopressinergic fibers are unknown. The vasopressinergic receptors detected in the brain are

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.

Microinjection of anti-vasopressin serum into hippocampus in mice: effects on appetitively reinforced task after intraventricular administration of Arg-vasopressin

Antiserum to [Arg8]vasopressin (anti-AVP) was bilaterally administered into dorsal hippocampus at 1:50 or 1:10 dilution 20 min before the 24-day retention session of a visual discrimination task. This treatment by itself did not affect the retention performance by comparison with the respective control group, whatever the dilution of anti-AVP, suggesting that hippocampal endogenous AVP is not involved in our behavioral paradigm. On the other hand, intracerebroventricular (i.c.v.) administration of AVP 10 min before the retention session improved retention performance of the visual discrimination task. When anti-AVP was injected at the 1:10 dilution into the dorsal hippocampus 10 min before the i.c.v. administration of AVP, the retention performance was not improved. These data suggest the involvement of the hippocampus in the behavioral expression of AVP following an i.c.v. treatment.

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.