[Sleepiness among adolescents: etiology and multiple consequences]. / La somnolence chez les adolescents: étiologie et conséquences multiples.

Over the past century a dramatic decline in sleep duration among adolescents, such as more than one hour of sleep loss per night, has been reported. A debt in sleep duration could lead to sleep deprivation, a major risk factor associated with daytime sleepiness. Sleepiness refers to the inability to maintain an adequate level of alertness during the day which may result in more or less being able to control falling asleep at inappropriate times. This literature review updates on sleepiness regarding its characteristics, etiology and consequences on adolescents. Studies revealed that from 25 % to 78 % of adolescents had reported sleepiness. Its manifestations may include heavy lids, yawns, difficulties to concentrate and emotional irritability. In addition, while it is recommended that adolescents under 18 years-old should sleep from eight to ten hours a night, only 63 % of them actually do so. The etiology of sleep deprivation and sleepiness in this population can be explained by various biological and societal factors. First, the sleep-wake cycle of adolescents shows a biological shift from the beginning of pubertal maturation, described as a perfect storm. It refers to a social jetlag by going to sleep and waking up later and accumulating a sleep debt during weekdays which they try to reimburse during weekends. This phenomenon can be explained by physiological changes such as a slower accumulation of sleep pressure. In addition to this perfect storm, environmental and societal factors contribute to the social jetlag and reduce sleep duration in adolescents. Screen exposure before bedtime can delay sleep and wake onset, which is a risk factor for sleeping debt. Substance use such as caffeine, cigarettes or electronic vaporizer, ADHD or freely available medication, alcohol, cannabis use or drug consumption could further disrupt sleep-wake cycle by stimulating, depressing or otherwise disrupting the central nervous system. Early, before 8:30 am, class start times have been associated with chronic sleep deprivation, higher level of sleepiness and delayed melatonin peak secretion. Adolescents working or doing extracurricular occupations for more than 20hours a week are more at risk for reduced sleep duration and sleepiness. Parental supervision about sleep during the weekdays were associated with more appropriate bedtime. Adolescents from low socio-demographic characteristics and from minority ethnic groups have reported displaying a shorter sleep duration. Finally, sleep disorders of a physiological origin such as narcolepsy, sleep apnea or restless legs syndrome, may explain the sleep deprivation and sleepiness. Sleep deprivation and sleepiness in adolescents have consequences on their health. Cognitive functioning, such as problem solving, attention or memory, as well as school performance, can be compromised by sleep deprivation and sleepiness. At the psychological level, adolescents reporting sleepiness are more prone to display mental health problems: associations were found between sleepiness and subjective perception of depression, anxiety, somatic complaints as well as with antisocial behaviors. Finally, 68 % of 16 year-old adolescents reported they drove a car, and the reported sleepiness could lead to road accidents due to reduced attentional functioning, reaction time and decision-making abilities. In the United-States, from 7 % to 16.5 % of deadly accidents were related to driving while drowsy. Highlighting etiology and problems associated with sleep deprivation and sleepiness in adolescents could guide researchers and clinicians towards the development of possible interventions. Public health measures and knowledge transfer programs regarding modifiable psychosocial and societal factors associated with sleep-wake bioregulation could increase awareness in parents as well as in political and societal decision makers.

Assessment and treatment of pediatric behavioral sleep disorders in Canada.

OBJECTIVES/BACKGROUND: This paper outlines the current state of Canadian training, clinical services, research, and advocacy initiatives related to non-respiratory sleep disorders, with a specific focus on insomnia, the most common sleep problem in children. METHODS: Information for this narrative review was collected from peer-reviewed publications, web-resources, and personal communications and experiences. RESULTS: It is estimated that approximately one-third of Canadian children and youth present with insomnia, and that this is impacting their physical and mental health, as well as learning in school. Training in pediatric sleep is limited and highly inconsistent within and across disciplines. While there are some publicly and privately funded pediatric sleep services available, these are mostly focused on respiratory sleep problems and are not equally accessible across the country. CONCLUSIONS: Pediatric assessment and treatment services for non-respiratory sleep disorders needs to be more integrated into the Canadian health care system.

The DSM5/RDoC debate on the future of mental health research: implication for studies on human stress and presentation of the signature bank.

In 2008, the National Institute of Mental Health (NIMH) announced that in the next few decades, it will be essential to study the various biological, psychological and social "signatures" of mental disorders. Along with this new "signature" approach to mental health disorders, modifications of DSM were introduced. One major modification consisted of incorporating a dimensional approach to mental disorders, which involved analyzing, using a transnosological approach, various factors that are commonly observed across different types of mental disorders. Although this new methodology led to interesting discussions of the DSM5 working groups, it has not been incorporated in the last version of the DSM5. Consequently, the NIMH launched the "Research Domain Criteria" (RDoC) framework in order to provide new ways of classifying mental illnesses based on dimensions of observable behavioral and neurobiological measures. The NIMH emphasizes that it is important to consider the benefits of dimensional measures from the perspective of psychopathology and environmental influences, and it is also important to build these dimensions on neurobiological data. The goal of this paper is to present the perspectives of DSM5 and RDoC to the science of mental health disorders and the impact of this debate on the future of human stress research. The second goal is to present the "Signature Bank" developed by the Institut Universitaire en Santé Mentale de Montréal (IUSMM) that has been developed in line with a dimensional and transnosological approach to mental illness.

The NAD(+) salvage pathway modulates cancer cell viability via p73.

The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.

Vagotomy prevents the effect of probiotics on caspase activity in a model of postmyocardial infarction depression.

BACKGROUND: Myocardial infarction (MI) is associated with apoptosis in the amygdala and, ultimately, with clinical signs of depression. Different treatments have proven to be beneficial in preventing depression, including combination of the probiotics Lactobacillus helveticus and Bifidobacterium longum for prophylaxis. We have speculated previously that the benefit of these probiotics is due to their anti-inflammatory properties, and evidence suggests that an intact vagus nerve is important for this effect to occur. This study was designed to ascertain vagus nerve involvement in the beneficial influence of probiotics on caspase activities in our post-MI animal model of depression. METHODS: Probiotics and/or vehicle were administered daily to male adult rats, 14 days before MI and until euthanasia. Vagotomy was performed in subgroups of rats 40 min before MI. They were sacrificed after 3 days of reperfusion, and MI size was assessed along with caspase-3 and -8 activities in the amygdala. KEY RESULTS: Probiotics had no effect on infarct size but vagotomy increased it. Caspase-3 and caspase-8 activities in the amygdala were higher in MI than in sham-operated rats, and this outcome was reversed by probiotics. The beneficial influence of probiotics was abolished by vagotomy. CONCLUSIONS & INFERENCES: Our data indicate that the effect of probiotics on caspase activities in the amygdala after MI depends on an intact vagus nerve.

Head Circumference in Canadian Male Adults: Development of a Normalized Chart / Circunferencia Cefálica en Hombres Adultos Canadienses: Desarrollo de una Tabla Normalizada

Macrocephaly has been reported as one of the few physiological markers of several syndromes which are identified during childhood. However, only a limited number of studies have investigated whether macrocephaly persists in adults in these conditions, due to an absence of up-to-date reference charts constructed for typically developing adults. Available adult head circumference reference charts either don't measure individuals beyond 21 years of age, are outdated, mostly use homogeneous samples and most importantly do not account for the individual's height and weight at the same time. Two hundred twenty-one male adults were recruited in a large urban community. For each participant, height, weight and head circumference were measured. A significant positive relationship was found between head circumference and height (r=0.379) as well as between head circumference and weight (r=0.391) and a weaker positive correlation with bodymass index (r=0.213). Charts to determine the level of head circumference abnormalities in adulthood are provided, along with a calculation formula for head circumference based on height and weight. The findings indicate the necessity of taking height and weight into account when measuring head circumference in adults.

La macrocefalia ha sido reportada como uno de los pocos marcadores fisiológicos de varios síndromes que se identifican durante la infancia. Sin embargo, sólo un número limitado de estudios han investigado si la macrocefalia persiste en los adultos con estas condiciones, debido a la ausencia de tablas de referencia actualizadas, construidas para el desarrollo normal de adultos. Las tablas de referencia de circunferencia cefálica disponible para adultos, no miden a los individuos más allá de los 21 años de edad, no están actualizadas, y la mayoría utiliza muestras homogéneas y lo más importante, no toman en cuenta al mismo tiempo la altura y peso del individuo. Fueron reclutados 221 hombres adultos de una comunidad urbana grande. En cada participante se midió la circunferencia cefálica, altura y peso. Se observó una relación significativamente positiva entre la circunferencia cefálica y la altura (r = 0,379), así como entre la circunferencia cefálica y el peso (r = 0,391), mientras la correlación positiva fue débil con el índice de masa corporal (r = 0,213). Se proporcionan tablas para determinar el nivel de anormalidades de la circunferencia cefálica en la edad adulta, junto con una fórmula de cálculo para la circunferencia cefálica basada en la altura y el peso. Los resultados indican la necesidad de tomar en cuenta altura y peso al momento de medir la circunferencia cefálica en adultos.

BLBP-expression in astrocytes during experimental demyelination and in human multiple sclerosis lesions.

Several lines of evidence indicate that remyelination represents one of the most effective mechanisms to achieve axonal protection. For reasons that are not yet understood, this process is often incomplete or fails in multiple sclerosis (MS). Activated astrocytes appear to be able to boost or inhibit endogenous repair processes. A better understanding of remyelination in MS and possible reasons for its failure is needed. Using the well-established toxic demyelination cuprizone model, we created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by Affymetrix GeneChip® arrays. One finding was the predominance of immune and stress response factors in the group of genes which were classified as remyelination-supporting factors. We further demonstrate that lesions with impaired remyelination capacity show weak expression of the radial-glia cell marker brain lipid binding protein (BLBP, also called B-FABP or FABP7). The expression of BLBP in activated astrocytes correlates with the presence of oligodendrocyte progenitor cells. BLBP-expressing astrocytes are also detected in experimental autoimmune encephalomyelitis during the remission phase. Furthermore, highest numbers of BLBP-expressing astrocytes were evident in lesions of early MS, whereas significantly less are present at the rim of (chronic)-active lesions from patients with long disease duration. Transfection experiments show that BLBP regulates growth factor expression in U87 astrocytoma cells. In conclusion, we provide evidence that expression of BLBP in activated astrocytes negatively correlates with disease duration and in parallel with remyelination failure.

Effects of different dietary ω-6/3 polyunsaturated fatty acids ratios on infarct size and the limbic system after myocardial infarction.

Changes in dietary omega-6/3 polyunsaturated fatty acids (PUFA) ratios affect anti- and proinflammatory equilibrium. As reperfused myocardial infarction (MI) is an inflammatory pathology that alters the cell integrity of the myocardium but also of other tissues, such as the hippocampus and amygdala, attenuation of the inflammation could be helpful in maintaining cell integrity after MI. Therefore, we hypothesized that a decrease in the dietary omega-6/3 PUFA ratio, without altering the diet content in total fat, proteins, or carbohydrates, will result in a reduction of infarct size and a diminution of postreperfusion apoptosis observed in the amygdala and hippocampus. Male Sprague-Dawley rats were fed 1 of 3 diets containing different omega-6/3 PUFA ratios for 2 weeks (5:1; 1:1; 1:5). Then, myocardial ischemia was induced by left anterior descending coronary artery occlusion for 40 min, followed by reperfusion. Cardioprotective mechanisms were studied in the myocardium at 15 min of reperfusion, along with myocardial infarct size after 24 h of reperfusion. Apoptosis was evaluated in the hippocampus and the amygdala. We found that infarct size was significantly reduced by 32% in groups 1:5 and 1:1 vs. group 5:1. Akt activity was higher in groups 1:5 and 1:1 compared with group 5:1. Caspase-3 enzymatic activity doubled in area CA1 and the dentate gyrus (DG) in group 5:1 compared with groups 1:1 and 1:5. In addition, caspase-8 enzymatic activity was increased in the DG at 24 h, and caspase-9 was enhanced in CA1 at 24 h in group 5:1 vs. groups 1:1 and 1:5. These results demonstrate that the increase in the dietary omega-3 PUFA, at the expense of omega-6 PUFA, reduces infarct size and helps to inhibit apoptosis in the limbic system after MI.

Tumor necrosis factor-alpha participates in apoptosis in the limbic system after myocardial infarction.

This study was designed to determine the role of tumor necrosis factor-alpha (TNFalpha) in apoptosis observed in the myocardium and limbic system after myocardial ischemia. PEG sTNFRI, a recombinant, human, soluble p55 Type 1 TNF receptor (3 mg/kg) or vehicle (saline) was administered s.c. to male Sprague-Dawley rats on days 5, 3 and 1 before myocardial ischemia. The animals were then subjected, under anesthesia, to left anterior descending coronary artery occlusion for 40 min, followed by 15-min or 72-h reperfusion. Caspase-3 and -8 activities as well as terminal dUTP nick-end labelling-positive cells were examined in the myocardium (subendocardial and subepicardial regions), lateral (LA) and medial amygdala (MA) and hippocampus (CA1, CA3, dentate gyrus (DG)). After 15 min of reperfusion, the subendocardial and CA1 regions presented an increase in caspase-3 activity, whereas caspase-8 activity appeared to be augmented in the DG. PEG sTNFRI inhibited caspase-8 activation in the DG. After 72 h of reperfusion, plasma TNFalpha levels were reduced in the treated groups. The DG, CA1, CA3 and MA showed an increment of caspase-8 activity, which was reversed by PEG sTNFRI, except in the MA. Furthermore, caspase-3 activity was increased in the CA1, DG, LA and MA. These results indicate that TNFalpha contributes to apoptosis via activation of the extrinsic pathway in the limbic system after myocardial infarction, which is not the case in the myocardium.

The effects of total sleep deprivation on recognition memory processes: a study of event-related potential.

This study examined the memorization of information after a night of normal sleep and total sleep deprivation (TSD) by means of event-related potentials (ERPs). We expected a disfacilitatory effect of TSD on memory processing. Eighteen subjects were tested twice in a counterbalanced fashion. During the study session, subjects were presented with unfamiliar face stimuli and asked to memorize them for a subsequent memory test. At the test session, the subjects were presented with the studied faces intermixed with "new" faces and asked to indicate the previously presented stimuli. The N100 was used as a covariate to control for the differences in level of vigilance between the two sessions. Sleep deprivation decreased subjects' ability to discriminate new from previously studied stimuli and decreased the peak amplitude of the early component (N200) to the decrement of performance. In addition, following TSD the amplitude of the late frontal component (LFC), which is thought to reflect contextual processing, was decreased in covariance with the N100 vigilance component. The amplitude of the late posterior component (LPC/P600) was also reduced but was unrelated to the vigilance component of the ERP. Based on prior studies, this LPC reduction can be interpreted to indicate a decrease in information retrieved after TSD. In summary, a night of TSD decreased the amplitude of the ERPs associated with complex episodic memory task stimuli, affected the frontal cortex during episodic retrieval, and prevented the elaboration process. Furthermore, there was an inability to discriminate what is and what is not in memory, possibly due to less local processing of details.

Behavioural signs of depression and apoptosis in the limbic system following myocardial infarction: effects of sertraline.

Depression is diagnosed in 15-30% of patients following myocardial infarction (MI) and this may also be observed in the rat. We measured the effects of the antidepressant sertraline on behavioural and biochemical events following MI in a rat model. Following surgery, MI rats and sham controls were treated with sertraline (10 mg/kg, i.p.) or saline. Subgroups of rats were tested for behavioural depression 14 days after surgery. Apoptosis was estimated in other rats by measuring caspase-3 activity and TUNEL positive cells (3 days after surgery) in limbic structures (amygdale, hippocampus, hypothalamus, frontal and prefrontal cortices). Bax/Bcl-2 ratio was measured 14 days after surgery. Behavioural signs of depression (decreased sucrose intake and forced swimming time) were found in saline-treated MI rats but not in sertraline-treated rats. Compared with controls, caspase-3 activity and TUNEL positive cells were significantly increased in most limbic structures of MI rats. High prefrontal Bax/Bcl-2 ratio in MI rats correlated with low forced swimming time. Apoptosis was not found in sertraline-treated MI rats. These results establish the bases of a rat model of depression following MI and show for the first time that a selective serotonin reuptake inhibitor prevents both behavioural and biochemical markers in this model.

Apoptosis time course in the limbic system after myocardial infarction in the rat.

Apoptosis is known to occur in the limbic system after myocardial infarction (MI) in the rat. Our study was designed to evaluate the time course dynamics of this phenomenon in limbic areas. Apoptosis, i.e., caspase-3 activity and the number of terminal dUTP nick-end labelling-positive cells, as well as brain-derived neurotrophic factor (BDNF) were quantitated in sham-operated controls and MI rats 1, 2 and 7 days after surgery. Both apoptosis parameters were increased throughout, although in different structures: the CA1 region of the hippocampus and the medial amygdala at day 1, the CA1 region of the hippocampus and the lateral amygdala at day 2, and the frontal cortex at day 7. At day 2, BDNF was decreased in the prefrontal cortex and medial amygdala, whereas it was elevated in the dentate gyrus of the hippocampus; at day 7, BDNF was reduced in the frontal cortex and posterior hypothalamus but was augmented in the medial amygdala. These data indicate that post-MI apoptosis in the limbic system is a dynamic process occurring mainly in the hippocampus and amygdala during the first days after MI. The fact that BDNF was increased as early as 2 days after MI suggests that neurogenesis can occur rapidly in selected limbic regions after MI.

Evolutionary conservation of alternative splicing in chicken.

Alternative splicing represents a source of great diversity for regulating protein expression and function. It has been estimated that one-third to two-thirds of mammalian genes are alternatively spliced. With the sequencing of the chicken genome and analysis of transcripts expressed in chicken tissues, we are now in a position to address evolutionary conservation of alternative splicing events in chicken and mammals. Here, we compare chicken and mammalian transcript sequences of 41 alternatively-spliced genes and 50 frequently accessed genes. Our results support a high frequency of splicing events in chicken, similar to that observed in mammals.

Reduction of apoptosis in the amygdala by an A2A adenosine receptor agonist following myocardial infarction.

It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A(2A) adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression. Thus, this study was designed to investigate whether cardioprotective A(2A) adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A(2A) agonist CGS21680 (0.2 mug/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared to the Control group (34.6 +/- 1.8% and 52.3 +/- 2.8% respectively; p < 0.05), with no difference compared to the Late group (40.1 +/- 6.1%). Apoptosis regression was documented in the amygdala of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive cell numbers were not reduced in the Late group. Moreover, TNFalpha was significantly reduced in the amygdala of the Early group compared to the Control and Late groups. These results indicate that A(2A) adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.

Involvement of the medial prefrontal cortex in two alternation tasks using different environments.

Spatial alternation performance in rats is usually evaluated with the T-Maze. The first aim of this study was to analyze the effect of a selective lesion of medial prefrontal cortex (mPFC) on performance in a T-maze. Second, we wanted to validate a new test using alternation in a water maze (AWM). The mPFC of 21 male Sprague-Dawley rats was lesioned bilaterally using in situ microinjection of ibotenic acid. Thirteen control rats received injections of the vehicle only. Results show that mPFC lesioned rats were significantly impaired in the T-Maze as well as in the AWM compared to controls. These results validate the AWM as a frontal cortex dependent task probing working memory and/or behavioral flexibility. We suggest that the AWM may be more powerful than the T-maze as an investigational tool, given that is can be easily compared to other water maze tasks that evaluate other (nonfrontal) cognitive modules.

Association of human DEAD box protein DDX1 with a cleavage stimulation factor involved in 3'-end processing of pre-MRNA.

DEAD box proteins are putative RNA helicases that function in all aspects of RNA metabolism, including translation, ribosome biogenesis, and pre-mRNA splicing. Because many processes involving RNA metabolism are spatially organized within the cell, we examined the subcellular distribution of a human DEAD box protein, DDX1, to identify possible biological functions. Immunofluorescence labeling of DDX1 demonstrated that in addition to widespread punctate nucleoplasmic labeling, DDX1 is found in discrete nuclear foci approximately 0.5 microm in diameter. Costaining with anti-Sm and anti-promyelocytic leukemia (PML) antibodies indicates that DDX1 foci are frequently located next to Cajal (coiled) bodies and less frequently, to PML bodies. Most importantly, costaining with anti-CstF-64 antibody indicates that DDX1 foci colocalize with cleavage bodies. By microscopic fluorescence resonance energy transfer, we show that labeled DDX1 resides within a Förster distance of 10 nm of labeled CstF-64 protein in both the nucleoplasm and within cleavage bodies. Coimmunoprecipitation analysis indicates that a proportion of CstF-64 protein resides in the same complex as DDX1. These studies are the first to identify a DEAD box protein associating with factors involved in 3'-end cleavage and polyadenylation of pre-mRNAs.

Spatial strategy elaboration in egocentric and allocentric tasks following medial prefrontal cortex lesions in the rat.

We evaluated the role of the medial prefrontal cortex (mPFC) in the elaboration of egocentric navigation strategies in a water maze (WM). Lesions of mPFC cell bodies was achieved in 21 rats using bilateral injections of ibotenic acid (IA); 13 control rats were injected with saline. After 17 days, rats had to learn an allocentric (using external cues: 10 lesioned, 7 saline rats) or an egocentric WM (using internal/kinetic cues: 10 lesioned, 6 saline rats) over six trials in a same session. The initial trajectory on the sixth trial was used as an index of the elaboration of a navigation strategy. In the egocentric test, lesioned rats were more rarely located in the target quadrant than control rats. No differences were found between lesioned and control rats in the allocentric test. These results show that lesions of the mPFC impairs the capacity to elaborate an egocentric navigation strategy.

Four hours of paradoxical sleep deprivation impairs alternation performance in a water maze in the rat.

Sixteen rats were deprived of paradoxical sleep (PS) for 4 h using the "flower pot" technique and 16 other served as yoked controls. PS-deprived and control rats then had to learn a water maze using either a standard allocentric configuration (i.e., finding the submerged platform using external cues; n = 6/group) or an alternation version (goal platform alternating between two locations; n 10/group). Rats were submitted to six trials with a cutoff time of 60 s and an intertrial interval of 5 min. Criterion was set as two consecutive successful completions. PS-deprived rats made more quadrant entries and took more time to reach criterion on the alternation task than control rats while both groups were equal on the allocentric task. Based on lesion studies (Ethier et al., this issue) we propose that tasks that require an intact medial prefrontal cortex are particularly sensitive to PS deprivation.

Differential regulation of the aldehyde dehydrogenase 1 gene in embryonic chick retina and liver.

Aldehyde dehydrogenase (ALDH1) is highly expressed in the dorsal cells of the undifferentiated retina, where it has been proposed to play a role in the formation of a retinoic acid gradient along the ventrodorsal axis. In contrast to the retina, ALDH1 levels increase with differentiation in the liver and remain elevated in the adult tissue. To understand the molecular basis for differential expression of ALDH1 during development, we characterized the ALDH1 transcripts expressed in chick retina and liver. By sequencing, primer extension, and S1 nuclease analysis, we show that retina ALDH1 mRNA has an additional 300 nucleotides of 5'-untranslated sequence resulting from the transcription of two 5' noncoding exons. There is a 24-29-kilobase pair (kb) gap between exons 1 and 2 and a 290-base pair gap between exons 2 and 3. Exon 3, which contains the ALDH1 start codon, represents the first exon of the liver transcript. Using a reporter gene assay, we have identified tissue-specific regulatory elements that govern ALDH1 expression in primary retina and liver cultures. Constructs with >1.6 kb of DNA flanking the 5'-end of exon 1 showed elevated activity in retinal cultures but only basal activity in liver cultures. In contrast, constructs with <1 kb of 5'-flanking DNA were active in both retina and liver cultures. Our results suggest that an important mechanism for the control of ALDH1 transcriptional activity is through the presence of inhibitory elements located 0.7-1.6 kb upstream of the ALDH1 gene. DNase I footprint analysis reveal four sites of protein-DNA interaction within this region, one of which is specific to the liver and corresponds to a NF-kappaB/Rel binding site.