Decreased Volume of Bone Marrow Adipocytes With Sparse Gelatinous Marrow Transformation in a Patient With Pancytopenia With Anorexia Nervosa: A Case Report.

Patients with anorexia nervosa (AN) often have complications of hematologic abnormalities and pancytopenia, which can be fatal. In patients with AN, the rates of anemia, leukopenia, and thrombocytopenia have been reported as 16.7-39%, 7.9-39%, and 5-11%, respectively; in patients with severe AN, the rates of anemia, leukopenia, thrombocytopenia, and pancytopenia have been reported as 47-83%, 49.5-79%, 16.8-25%, and 16.4-23%, respectively. Hematologic abnormalities are often associated with morphological myeloid transformations such as hypoplasia, aplasia, and gelatinous marrow transformation (GMT). Hypocellularity, such as hypoplastic or aplastic, often results in a dry tap, whereas GMT does not usually result in this because of the aspiration of gelatinous material. Therefore, bone marrow aspiration in patients with pancytopenia with AN usually does not show a dry tap. The bone marrow adipocyte (BMA) volume increases in patients with AN, except in those with severe malnutrition. Patients with AN experiencing pancytopenia often exhibit GMT associated with atrophy of the originally increased volume of BMAs. Herein, we report the case of a patient with pancytopenia with AN who exhibited a dry tap on bone marrow aspiration. A bone marrow biopsy revealed sparse GMT with decreased BMA volume and areas of hematopoietic cells, adipocytes, and no GMT. A 13-year-old Japanese girl weighing 25.8 kg (BMI: 10.0 kg/m2) was admitted to our hospital and received nutritional therapy. The patient presented with pancytopenia and fever, prompting the conduct of bone marrow examinations. Bone marrow aspiration resulted in a dry tap, and the bone marrow biopsy revealed sparse GMT with a decreased volume of BMAs. Additionally, an area devoid of hematopoietic cells, adipocytes, or GMT was observed. Nutritional therapy resulted in weight gain and improved pancytopenia. Upon discharge, the patient weighed 40.0 kg (BMI: 15.5 kg/m2) with a normal WBC count, hemoglobin levels, and platelet count. It is significant to study hematological and bone marrow changes because patients with AN often present with hematologic abnormalities. The identification of sparse GMT, which is associated with a decrease in BMA volume and the presence of an area devoid of hematopoietic cells, adipocytes, or GMTs, is a novel finding. The improvement in pancytopenia following nutritional therapy suggests a link between myeloid transformation and malnutrition. Consequently, in patients with pancytopenia associated with AN exhibiting these bone marrow findings, nutritional therapy is necessary.

Mood and physiological effects of visual stimulation with images of the natural environment in individuals with depressive and anxiety disorders.

BACKGROUND: Nature therapies are gaining attention as non-pharmacological treatments for depressive and anxiety disorders, but research on their effectiveness in patients is limited. This study investigates the mood-improving effects of visual stimulation with natural environmental images in patients with depressive and anxiety disorders. METHODS: We conducted a randomized crossover comparison trial involving 60 right-handed adult participants with depressive or anxiety disorders and receiving outpatient treatment. Visual stimuli of natural environments consisted of green-themed nature images, while the control stimuli featured urban scenes dominated by buildings. The stimulation lasted for 3 min, during which orbital prefrontal brain activity was measured using a 2-channel Near-infrared Spectroscopy (NIRS) system, and heart rate variability was assessed using fingertip accelerated plethysmography. RESULTS: Mood enhancement effects were observed in both the depressive and anxiety disorder groups following visual stimulation with nature images. In the depression group, orbital prefrontal oxygenated hemoglobin concentration significantly increased after visual stimulation with nature images, while there were no significant changes in the anxiety group. However, in the anxiety group, a correlation was found between reduced orbital prefrontal oxygenated hemoglobin in response to nature images and increased mood-enhancement. Furthermore, the severity of depressive symptoms did not significantly affect the intervention effects, whereas heightened anxiety symptoms was associated with a smaller mood enhancement effect. DISCUSSION: Our study demonstrates the benefits of nature image stimulation for patients with depressive and anxiety disorders. Differential orbital prefrontal brain activity impacts notwithstanding, both conditions exhibited mood enhancement, affirming the value of nature image stimulation.

Evaluating the impact of a short bout of stair-climbing on creative thinking in a between-subjects pretest posttest comparison study.

Recent studies have indicated potential links between short bouts of physical activity like stair-climbing and enhanced creative thinking. However, previous research featured limitations, such as using an uncommon 3 flights round-trip design and lacking baseline creative thinking evaluations. To rectify these limitations and build a more comprehensive understanding, the present study adopts a between-subjects pretest posttest comparison design to scrutinize the effects of ascending stair-climbing on both divergent and convergent thinking. 52 subjects underwent a pretest, followed by random assignment to one of four interventions: ascending stair-climbing for 2, 5, or 8 flights, or taking an elevator for 8 flights, before progressing to a posttest. The results revealed a notable improvement in convergent thinking, measured by the increased number of solved matchstick arithmetic problems (d = 1.165), for participants who climbed 2 flights of stairs compared to those who took the elevator. However, climbing 5 or 8 flights showed no such impact on convergent thinking, and stair-climbing, regardless of the number of flights, did not influence divergent thinking. These findings underscore the utility of brief stair-climbing as an accessible means to enhance convergent thinking in everyday settings, providing a nuanced insight into the relationship between physical activity and creative thinking processes.

The Effect of Brief Stair-Climbing on Divergent and Convergent Thinking.

Recent studies show that even a brief bout of aerobic exercise may enhance creative thinking. However, few studies have investigated the effect of exercise conducted in natural settings. Here, in a crossover randomized controlled trial, we investigated the effect of a common daily activity, stair-climbing, on creative thinking. As experimental intervention, subjects were asked to walk downstairs from the fourth to the first floor and back at their usual pace. As control intervention, they walked the same path but using the elevator instead. Compared to using the elevator, stair-climbing enhanced subsequent divergent but not convergent thinking in that it increased originality on the Alternate Use Test (d = 0.486). Subjects on average generated 61% more original uses after stair-climbing. This is the first study to investigate the effect of stair-climbing on creative thinking. Our findings suggest that stair-climbing may be a useful strategy for enhancing divergent thinking in everyday life.

Clinically significant changes in pain along the Pain Intensity Numerical Rating Scale in patients with chronic low back pain.

Low back pain (LBP) is the most common cause of chronic pain. Numerous clinical scales are available for evaluating pain, but their objective criteria in the management of LBP patients remain unclear. This study aimed to determine an objective cutoff value for a change in the Pain Intensity Numerical Rating Scale (ΔPI-NRS) three months after LBP treatment. Its utility was compared with changes in six commonly used clinical scales in LBP patients: Pain Disability Assessment Scale (PDAS), Pain Self-Efficacy Questionnaire (PSEC), Pain Catastrophizing Scale (PCS), Athens Insomnia Scale (AIS), EuroQoL 5 Dimension (EQ5D), and Locomo 25. We included 161 LBP patients treated in two representative pain management centers. Patients were partitioned into two groups based on patient's global impression of change (PGIC) three months after treatment: satisfied (PGIC = 1, 2) and unsatisfied (3-7). Multivariate logistic regression analysis was performed to explore relevant scales in distinguishing the two groups. We found ΔPI-NRS to be most closely associated with PGIC status regardless of pre-treatment pain intensity, followed by ΔEQ5D, ΔPDAS, ΔPSEC, and ΔPCS. The ΔPI-NRS cutoff value for distinguishing the PGIC status was determined by ROC analysis to be 1.3-1.8 depending on pre-treatment PI-NRS, which was rounded up to ΔPI-NRS = 2 for general use. Spearman's correlation coefficient revealed close relationships between ΔPI-NRS and the six other clinical scales. Therefore, we determined cutoff values of these scales in distinguishing the status of ΔPI-NRS≥2 vs. ΔPI-NRS<2 to be as follows: ΔPDAS, 6.71; ΔPSEC, 6.48; ΔPCS, 6.48; ΔAIS, 1.91; ΔEQ5D, 0.08; and ΔLocomo 25, 9.31. These can be used as definitive indicator of therapeutic outcome in the management of chronic LBP patients.

Altered plasma protein glycosylation in a mouse model of depression and in patients with major depression.

BACKGROUND: Glycosylation is a common posttranslational modification in protein biosynthesis that is implicated in several disease states. It has been reported that specific protein glycan structures are useful as biomarkers for cancer and some neuropsychiatric diseases; however, the relationship between plasma protein glycosylation and major depressive disorder (MDD) has not been investigated to date. The aim of this study was to determine whether plasma protein glycan structures are altered in depression using a stress-based mouse model and samples from patients with MDD. METHODS: We used chronic ultra-mildly stressed mice that were untreated or treated with imipramine as mouse models of depression and remission, respectively. We also made comparisons between samples from depressed and remitted patients with MDD. Protein glycosylation was analyzed using a lectin microarray that included 45 lectins with binding affinities for various glycan structures. RESULTS: Sia-alpha2-6Gal/GalNAc was a commonly altered glycan structure in both depression model mice and patients with MDD. Moreover, the expression of ST6GALNAC2 was decreased in leukocytes from patients with MDD. LIMITATIONS: Our study samples were small and we did not identify specific alpha2-6Gal/GalNAc-sialylated proteins. CONCLUSIONS: The glycan structure Sia-alpha2-6GalNAc in plasma protein and ST6GALNAC2 expression in peripheral leukocytes may have utility as candidate biomarkers for the clinical diagnosis and monitoring of MDD.

Disconnectivity between Dorsal Raphe Nucleus and Posterior Cingulate Cortex in Later Life Depression.

The dorsal raphe nucleus (DRN) has been repeatedly implicated as having a significant relationship with depression, along with its serotoninergic innervation. However, functional connectivity of the DRN in depression is not well understood. The current study aimed to isolate functional connectivity of the DRN distinct in later life depression (LLD) compared to a healthy age-matched population. Resting state functional magnetic resonance imaging (rsfMRI) data from 95 participants (33 LLD and 62 healthy) were collected to examine functional connectivity from the DRN to the whole brain in voxel-wise fashion. The posterior cingulate cortex (PCC) bilaterally showed significantly smaller connectivity in the LLD group than the control group. The DRN to PCC connectivity did not show any association with the depressive status. The findings implicate that the LLD involves disruption of serotoninergic input to the PCC, which has been suggested to be a part of the reduced default mode network in depression.

Identification of commonly altered genes between in major depressive disorder and a mouse model of depression.

The heterogeneity of depression (due to factors such as varying age of onset) may explain why biological markers of major depressive disorder (MDD) remain uncertain. We aimed to identify gene expression markers of MDD in leukocytes using microarray analysis. We analyzed gene expression profiles of patients with MDD (age ≥50, age of depression onset <50) (N = 10, depressed state; N = 13, remitted state). Seven-hundred and ninety-seven genes (558 upregulated, 239 downregulated when compared to those of 30 healthy subjects) were identified as potential markers for MDD. These genes were then cross-matched to microarray data obtained from a mouse model of depression (676 genes, 148 upregulated, 528 downregulated). Of the six common genes identified between patients and mice, five genes (SLC35A3, HIST1H2AL, YEATS4, ERLIN2, and PLPP5) were confirmed to be downregulated in patients with MDD by quantitative real-time polymerase chain reaction. Of these genes, HIST1H2AL was significantly decreased in a second set of independent subjects (age ≥20, age of onset <50) (N = 18, subjects with MDD in a depressed state; N = 19, healthy control participants). Taken together, our findings suggest that HIST1H2AL may be a biological marker of MDD.

Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice.

UNLABELLED: Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3ß (GSK3ß) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3ß expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress. SIGNIFICANCE STATEMENT: Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3ß, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.

Disrupted orbitomedial prefrontal limbic network in individuals with later-life depression.

BACKGROUND: Depression in old age is an increasing contributor to poor health and accompanying health care costs. Although there is an abundance of literature on later-life depression (LLD), the neural correlates have not been clarified. The aim of this study was to determine whether patients with LLD show abnormal gray matter volume (GMV) and white matter integrity by using multiple image analysis methods. METHODS: The study included 45 patients with LLD and 61 healthy participants who were matched for age, sex, years of education, and vascular risk factors. GMV was examined using voxel-based morphometry, while the white matter integrity was determined by tract-based spatial statistics and tract-specific analysis, which were obtained from high-resolution magnetic resonance images. RESULTS: Patients with LLD showed significantly less GMV in the orbitofrontal cortex, anterior cingulate, insula, amygdala, and temporal regions, as well as higher fractional anisotropy in the uncinate fasciculus, compared with healthy participants. Patients with LLD who had reduced orbitofrontal and insular GMV had more severe clinical variables. The reduced orbitofrontal GMV was associated with higher fractional anisotropy in the uncinate fasciculus. LIMITATION: The effects of medication should also be considered when interpreting the results of this study. CONCLUSION: Our results suggest that regional GMV is linked to white matter integrity of the uncinate fasciculus in the orbitomedial prefrontal limbic network, and the disruption of this network may be involved in the pathophysiology of LLD.

Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior.

BACKGROUND: Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Recent evidence has suggested that sirtuins (SIRTs) play a key role in cognition and synaptic plasticity, yet their role in mood regulation remains controversial. Here, we aimed to investigate whether SIRT function is associated with chronic stress-elicited depression-like behaviors and neuronal atrophy. METHODS: We measured SIRT expression and activity in a mouse model of depression. We injected mice with a SIRT1 activator or inhibitor and measured their depression-like behaviors and dendritic spine morphology. To assess the role of SIRT1 directly, we used a viral-mediated gene transfer to overexpress the wild-type SIRT1 or dominant negative SIRT1 and evaluated their depression-like behaviors. Finally, we examined the role of extracellular signal-regulated protein kinases 1 and 2, a potential downstream target of SIRT1, in depression-like behavior. RESULTS: We found that chronic stress reduced SIRT1 activity in the dentate gyrus of the hippocampus. Pharmacologic and genetic inhibition of hippocampal SIRT1 function led to an increase in depression-like behaviors. Conversely, SIRT1 activation blocked both the development of depression-related phenotypes and aberrant dendritic structures elicited by chronic stress exposure. Furthermore, hippocampal SIRT1 activation increased the phosphorylation level of extracellular signal-regulated protein kinases 1 and 2 in the stressed condition, and viral-mediated activation and inhibition of hippocampal extracellular signal-regulated protein kinase 2 led to antidepressive and prodepressive behaviors, respectively. CONCLUSIONS: Our results suggest that the hippocampal SIRT1 pathway contributes to the chronic stress-elicited depression-related phenotype and aberrant dendritic atrophy.

[Clinical examination of 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide poisoning, who recovered from severe neurocognitive impairment by repetitive hyperbaric oxygen therapy].

We performed hyperbaric oxygen (HBO) therapy for 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide (CO) poisoning. All patients were male and around 50 years old, and they had not received HBO therapy within 24 h after CO poisoning, even though they showed severe consciousness disturbance. In these patients, delayed neuropsychiatric encephalopathy appeared about 25 days after acute CO poisoning, and HBO therapy was initiated within 8 days after disease onset. Although the condition of 2 of the patients worsened initially, they showed significant improvement of neurocognitive impairment after 30 sessions of HBO therapy. The clinical courses of these patients suggest that the effect of HBO therapy can be evaluated after 30 sessions. To evaluate the validity of the indices of the clinical effect of HBO therapy, we performed brain magnetic resonance imaging, single photon emission computed tomography, electroencephalography (EEG), and neurocognitive tests (HDS-R, and Wechsler Adult Intelligence Scale-Revised or III). Our results showed that changes in EEG signals and neurocognitive tests were closely correlated with the patients' clinical courses.

The alteration of hypoxia inducible factor-1 (HIF-1) and its target genes in mood disorder patients.

Recent studies suggest that the dysfunction of neural plasticity is associated with mood disorders. Hypoxia-inducible factor-1 (HIF-1), which is a transcriptional activator of vascular endothelial growth factor (VEGF), activates the cellular response to hypoxia. HIF-1 is ubiquitously expressed in all cells, including peripheral leukocytes. However, little is known about the role of HIF-1 in mood disorder. In the present study, we investigated the mRNA expression levels of HIF-1 (α and ß) and its target genes (VEGF, GLUT1, PGK1, PFKFB3, and LDHA) in the peripheral white blood cells of patients with major depressive disorder (MDD) and bipolar disorder (BPD). We found increased expression of HIF- 1α and HIF-1ß mRNA, as well as the target genes, VEGF, and PFKFB3 in both MDD and BPD patients in a depressive state compared to healthy control subjects. Furthermore, the mRNA expression levels of GLUT1, PGK1, and LDHA were increased in MDD patients in a depressive state compared to healthy control subjects. We also found increased expression of HIF-1α and LDHA mRNA in MDD patients in a remissive state, whereas the mRNA expression levels of other genes in a remissive state were comparable to those in healthy control subjects. There was no significant difference in mRNA expression levels of the genes examined among patients receiving any type of antidepressant or mood stabilizer. Our data suggest that altered expression of HIF-1 and its target genes mRNA in peripheral blood cells are associated-mainly in a state-dependent manner-with mood disorders (especially with MDD). In addition, altered expression of HIF-1 and its target genes may be associated with the pathophysiology of depression.

[Functional biomarkers of mood disorders: differential diagnosis and clinical classification with gene expression in peripheral leukocytes].

In order to identify the possible biomarkers of mood disorders, we measured the mRNA levels for a variety of genes in peripheral leukocytes of mood disorder patients in a depressive, as well as in a remissive state, comparing with healthy controls. We selected and measured the levels of genes of interest, which are listed as follows: glucocorticoid receptor, neurotrophic factors, cell adhesion molecules, SR protein splicing factors, transcription factors, epigenetic factors (histone deacetylase, sirtuin, DNA methyltransferase), since these molecules are suggested to be associated with the neural function, synaptic plasticity, and behaviors in animal models, as well as with the pathophysiology and pathogenesis of mood disorders. We found the three different types of biological markers: 1) state markers those revealed alterations of gene expression only in a depressive state of major depressive patients and/or bipolar depressive patients, 2) trait markers those showed altered gene expression both in a depressive and a remissive state of major depressive patients and/or bipolar depressive patients, and 3) markers of the treatment resistance those revealed different alterations of gene expression between treatment resistant and treatment responsive patients in a depressive state. The use of state and trait markers in combination would allow us to put a differential diagnosis between major depressive and bipolar depressive states, as well as between mood disorders and neurotic depressive states. Furthermore, candidate biomarkers of treatment resistance could be used to consider forward of applying the electric convulsive therapy even in an early stage of a depressive state.

State-dependent changes in the expression of DNA methyltransferases in mood disorder patients.

Aberrant transcriptional regulation may be one of the key components of the pathophysiology of mood disorders. DNA methylation generally acts as an epigenetic gene silencing mechanism and is catalyzed by a group of enzymes known as DNA methyltransferases (DNMTs). Several lines of evidence have suggested aberrant DNA methylation in patients with neuropsychiatric disorders and in animal models for psychiatric disorders. However, the involvement of DNMTs in the pathophysiology of mood disorders is not completely understood. In this study, we aimed to determine whether there are alterations in the expression of DNMTs mRNA in mood disorder patients. We used quantitative real-time PCR to measure the mRNA expression of four DNMT isoforms in the peripheral white blood cells of major depressive disorder (MDD) and bipolar disorder (BPD) patients during a depressive and a remissive episode. We found that the levels of DNMT1 mRNA were significantly decreased in a depressive but not in a remissive state of MDD and BPD. In addition, the levels of DNMT3B mRNA in MDD were significantly increased in a depressive but not in a remissive state. Thus, our data suggest that the altered expression of DNMTs is state dependent and that the aberrant epigenetic gene regulations caused by the altered expression of DNMT1 and DNMT3B may be associated with the pathophysiology of mood disorders.

Altered sirtuin deacetylase gene expression in patients with a mood disorder.

Sirtuins are a family of NAD+-dependent enzymes that regulate cellular functions through deacetylation of various proteins. Although recent reports have suggested an important role of deacetylases (i.e., histone deacetylases) in mood disorders and antidepressant action, the involvement of sirtuins in the pathophysiology of mood disorders is largely unknown. In this study, we aimed to determine whether there are alterations in sirtuin mRNA expression in peripheral white blood cells of patients with a mood disorder. Also, to examine whether the altered sirtuin mRNA expression is state- or trait-dependent, mood disorder patients who were in a remissive state were assessed. We used quantitative real-time polymerase chain reaction to measure the mRNA levels of seven sirtuin isoforms (SIRT1-7) in peripheral white blood cells of patients with major depressive disorder (MDD) or bipolar disorder (BPD) during depressive and remissive states and in normal healthy subjects. The SIRT1, 2 and 6 mRNA levels in MDD and BPD patients decreased significantly in those who were in a depressive state compared to healthy controls, whereas the expression of those mRNAs in both MDD and BPD of patients in a remissive state were comparable to those in healthy controls. Thus, our data suggest that altered SIRT1, 2 and 6 expression is state-dependent and might be associated with the pathogenesis and/or pathophysiology of mood disorders.

Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1(-/-) mice. In addition, HSF1(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.