Distinct Functions of Egr Gene Family Members in Cognitive Processes

The different gene members of the Egr family of transcriptional regulators have often been considered to have related functions in brain, based on their co-expression in many cell-types and structures, the relatively high homology of the translated proteins and their ability to bind to the same consensus DNA binding sequence. Recent research, however, suggest this might not be the case. In this review, we focus on the current understanding of the functional roles of the different Egr family members in learning and memory. We briefly outline evidence from mutant mice that Egr1 is required specifically for the consolidation of long-term memory, while Egr3 is primarily essential for short-term memory. We also review our own recent findings from newly generated forebrain-specific conditional Egr2 mutant mice, which revealed that Egr2, as opposed to Egr1 and Egr3, is dispensable for several forms of learning and memory and on the contrary can act as an inhibitory constraint for certain cognitive functions. The studies reviewed here highlight the fact that Egr family members may have different, and in certain circumstances antagonistic functions in the adult brain

Paradoxical Role of an Egr Transcription Factor Family Member, Egr2/Krox20, in Learning and Memory

It is well established that Egr1/zif268, a member of the Egr family of transcription factors, is critical for the consolidation of several forms of memories. Recently, the Egr3 family member has also been implicated in learning and memory. Because Egr family members encode closely related zinc-finger transcription factors sharing a highly homologous DNA binding domain that recognises the same DNA sequence, they may have related functions in brain. Another Egr family member expressed in brain, Egr2/Krox20 is known to be crucial for normal hindbrain development and has been implicated in several inherited peripheral neuropathies; however, due to Egr2-null mice perinatal lethality, its potential role in cognitive functions in the adult has not been yet explored. Here, we generated Egr2 conditional mutant mice allowing postnatal, forebrain-specific Cre-mediated Egr2 excision and tested homozygous, heterozygous and control littermates on a battery of behavioural tasks to evaluate motor capacity, exploratory behaviour, emotional reactivity and learning and memory performance in spatial and non-spatial tasks. Egr2-deficient mice had no sign of locomotor, exploratory or anxiety disturbances. Surprisingly, they also had no impairment in spatial learning and memory, taste aversion memory or fear memory using a trace conditioning paradigm. On the contrary, Egr2-deficient mice had improved performance in motor learning on a rotarod, and in object recognition memory. These results clearly do not extend the phenotypic consequences resulting from either Egr1 or Egr3 loss-of-function to Egr2. In contrast, they indicate that Egr family members may have different, and in certain circumstances antagonistic functions in the adult brain

Expérience précoce et ontogenèse des comportements défensifs chez la seiche (Sepia officinalis) (approches comportementale et neurobiologique)

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Genes, Plasticity and Mental Retardation.

International audienceFunctional and structural plasticity is a fundamental property of the brain involved in diverse processes ranging from brain construction and repair to storage of experiences during lifetime. Our current understanding of different forms of brain plasticity mechanisms has advanced tremendously in the last decades, benefiting from studies of development and memory storage in adulthood and from investigations of diverse diseased conditions. In this review, we focus on the role of mental retardation (MR) genes and show how this developing area of research can enrich our knowledge of the cellular and molecular mechanisms of brain plasticity and cognitive functions, and of the dysfunctional mechanisms underlying MR. We describe two main groups of MR genes; those leading to dysfunctional neurodevelopmental programs and brain malformations, and those which rely on alterations in molecular mechanisms underlying synaptic organization and plasticity. We first explore the role of MR genes in key mechanisms of neurogenesis and neuronal migration during development and in the adult, such as actin and microtubule-cytoskeletal dynamics and signal transduction. We then define the contribution of MR genes to forms of activity-dependent synaptic modifications, such as those involved in molecular organization of the synapse, intracellular signaling regulating gene programs and neuronal cytoskeleton to control network remodeling. We trace the characteristics of MR genes playing key roles in many forms of brain plasticity mechanisms, and highlight specific MR genes that endorse distinct roles in different cell types or brain regions, and at various times of a brain lifetime

Early Experience and Postembryonic Maturation of Body Patterns in Cuttlefish (Sepia officinalis).

International audienceThis study investigates effects of the environment on the maturation of body patterns in cuttlefish (Sepia officinalis). Cuttlefish were reared either individually on a uniform background, which the authors have termed uniform-solitary conditions (Group A), or grouped on variegated backgrounds, which the authors have termed varied-social conditions (Group B). At Days 1, 15, 30, and 60, juveniles were placed individually in perceptually different testing conditions, either on small, variegated stones or on a uniform pale gray background. During development in both testing conditions, juveniles from Group B concealed themselves differently from those from Group A. Thus, it appears that the response to the background is subject to individual experience. Some hypotheses are discussed relating to the effect of early experience on the maturation of body patterns

Effects of rearing conditions on sand digging efficiency in juvenile cuttlefish

International audienceThe effect of environment on the maturation of sand digging behaviour in cuttlefish was studied. Sand digging behaviour of cuttlefish individually reared on sand was daily observed in their rearing tanks (first study). Other cuttlefish were individually reared from hatching to 2 weeks of life in different conditions (Group A, on a sandy substrate and group B, without sand). At days 0, 3, 6, 9, 12 and 15, cuttlefish from Groups A and B were placed in a novel tank, the bottom of which was covered by sand (second study). The first study shows that more and more cuttlefish sand dig in their rearing tank during the first 6 days of life. The second study shows that, confronted with a novel sand bottom, cuttlefish from Group A show shorter latencies of sand digging and they cover more completely than do cuttlefish from Group B. This indicates that the developmental changes in sand digging appear not totally pre-programmed, but at least partially experience-dependent. Presence of sand in rearing tanks may allow cuttlefish to acquire experience of digging to make this behaviour more efficient

Brain maturation and early experience in cuttlefish (Sepia officinalis)

International audienceIn cephalopods, previous studies have shown the implication of different brain structures in learning and memory. In the present work, we examined in the cuttlefish whether enriched early experience affects neurogenesis in these structures during the first weeks of post-embryonic development. In this aim, we have adapted the bromodeoxyuridine (BrdU) immunohistochemical technique to the cuttlefish. BrdU is a thymidine analog which is incorporated into DMA during the S-phase of the cell cycle. Then, immunodetection of BrdU some hours after injection reveals the cells produced during the integration time of BrdU. Newly hatched and fifteen-day old cuttlefish reared either in impoverished or enriched environment were injected with BrdU. 24 hours after injection, cuttlefish were killed, and BrdU was immunohistochemicaly detected. Densities of BrdU labelled cells in the optic, vertical and superior frontal lobes were determined with an image analyser. During the two first weeks of post-embryonic development, neurogenesis decreases in the three brain structures mentioned above. However, as soon as fifteen days of age, this phenomenon is attenuated in these lobes for animals reared in enriched conditions. Our results show the influence of early experience enrichment on post-embryonic neurogenesis in structures classically involved in learning and memory processes in cuttlefish

Effect of early feeding experience on subsequent prey preference by cuttlefish, Sepia officinalis

International audienceFood preferences were investigated in cuttlefish during the first 3 months' posthatching, using choice tests between crabs, shrimps, and young fish. The results showed that without previous feeding experience, cuttlefish preferred shrimps on Day 3. This suggests an innate food preference; however, it was possible to induce a preference for an originally nonpreferred prey item in 3-day-old and naïve cuttlefish, demonstrating the flexibility of this initial behavioral preference in response to previous individual experience. This preference suggests a learning process involving a form of long-term memory, demonstrated for the first time in juvenile cuttlefish. Until Day 30, juvenile cuttlefish fed exclusively shrimps chose shrimps. This preference probably depends on their previous feeding experience. Finally, it appears that from Day 60, cuttlefish reared on the same restricted diet have a tendency to switch their preference to novel prey items, which diversify their diet

The effect of early feeding experience on subsequent prey preference in cuttlefish, Sepia officinalis

International audienceWe investigated the effect of early feeding experience on subsequent prey preference in juveniles of Sepia officinalis. First, choice tests between 3 prey items were conducted at day 3 in naive juveniles and at days 6, 30, 60 and 90 of post-embryonic development in cuttlefish only fed shrimps, their originally preferred prey. The results show that without any prior experience cuttlefish preferred shrimps at 3 days and throughout the first week of post-embryonic development; this suggests that their choice could be guided by a ‘hard-wired’ program at least during the first week of life. This ‘innate’ preference can however be modified by early individual experience. We indeed induced a preference for the originally least preferred prey (crabs) in naïve cuttlefish. This ‘new’ preference may correspond to some learning processes, involving a form of long-term memory trace of it in 7-day old cuttlefish. This is the first demonstration of the existence of a kind of long-term memory in such young cuttlefish. Last, it appears that after one month, although they have only been fed shrimps so far, i.e. their originally prey preference, cuttlefish have a tendency to switch their preference to novel prey and then to diversify their diet

Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats

International audienceHypothyroidism is a condition that becomes more prevalent with age. Patients with untreated hypothyroidism have consistently reported symptoms of severe cognitive impairments. In patients suffering hypothyroidism, thyroid hormone supplementation offers the prospect to alleviate the cognitive consequences of hypothyroidism; however, the therapeutic value of TH supplementation remains at present uncertain and the link between cellular modifications associated with hypothyroidism and neurodegeneration remains to be elucidated. In the present study, we therefore evaluated the molecular and behavioral consequences of T3 hormone replacement in an animal model of hypothyroidism. We have previously reported that the antithyroid molecule propylthiouracil (PTU) given in the drinking water favors cerebral atrophy, brain neuroinflammation, Aβ production, Tau hyperphosphorylation, and altered plasticity-related cell-signaling pathways in the hippocampus in association with hippocampal-dependent spatial memory deficits. In the present study, our aim was to explore, in this model, the effect of hippocampal T3 signaling normalization on various molecular mechanisms involved in learning and memory that goes awry under conditions of hypothyroidism and to evaluate its potential for recovery of hippocampal-dependent memory deficits. We report that T3 supplementation can alleviate hippocampal-dependent memory impairments displayed by hypothyroid rats and normalize key markers of thyroid status in the hippocampus, of neuroinflammation, Aβ production, and of cell-signaling pathways known to be involved in synaptic plasticity and memory function. Together, these findings suggest that normalization of hippocampal T3 signaling is sufficient to reverse molecular and cognitive dysfunctions associated with hypothyroidism