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1.
J Psychiatr Res ; 113: 10-16, 2019 06.
Article in English | MEDLINE | ID: mdl-30878787

ABSTRACT

The positive effect of exercise on human health and the relationship between physical activity, health, and wellbeing are well studied and extensively documented in the literature. However, considerably less attention is devoted to the impact of exercise on mental health and wellbeing for people experiencing a mental illness, in general, and in particular for inpatients in the mental health care system. Here, we determine the clinical feasibility and effects of short-term (up to three months) vs long-term (up to six months) group-based exercise program for inpatients with chronic mental health. Changes in psychiatric symptoms, well-being, empathy, and physiological fitness factor (e.g., fasting blood glucose, lipid profile, hemoglobin A1C, and BMI) were monitored before, during and following the physical exercise program. Here, we demonstrated that long-term physical activity improved negative symptoms, but not positive symptoms, while improvement in the severity of the illness as measured by the BPRS questionnaire was found to be independent of the training time. We additionally showed that the empathic ability of patients who exercised for more than three months was significantly improved as compared to the other experimental groups. No significant differences were found in wellbeing, mood, satisfaction, and functioning between exercise groups and the control group. Furthermore, physical activity did not improve any of the physiological parameters that were measured in this study. Together, these data indicate that exercise for at least 3 months seems to improve the overall patient mental state, but not his or her physiological parameters, while improvement in negative symptoms and patient's empathy may occur only after a long-term physical exercise activity.


Subject(s)
Exercise Therapy/methods , Exercise Therapy/psychology , Health Status , Inpatients/psychology , Mental Disorders/psychology , Mental Disorders/therapy , Adult , Blood Glucose , Body Mass Index , Empathy , Feasibility Studies , Female , Glycated Hemoglobin , Hospitals, Psychiatric , Humans , Inpatients/statistics & numerical data , Israel , Lipids/blood , Male , Mental Disorders/blood , Middle Aged , Pilot Projects , Quality of Life/psychology , Surveys and Questionnaires , Treatment Outcome , Young Adult
2.
Brain Behav Immun ; 79: 207-215, 2019 07.
Article in English | MEDLINE | ID: mdl-30738182

ABSTRACT

Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g. schizophrenia and autism) in the offspring. In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alteration of the exposed MIA mice at juvenile and adulthood. We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material in fetal brain. At the behavioral levels, adult late-MIA-exposed female offspring, but not juvenile, display lack preference to a novel object. While working memory alteration observed only in adult male MIA-exposed offspring at late gestation day. In addition, we found that adult females MIA-exposed mice spent more time in the center of the open field than female-saline groups. On the other hand, juvenile male offspring exposed to MIA at early, but not late, gestation day displayed a significant alteration in social interaction. Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes, and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.


Subject(s)
Neuregulins/immunology , Prenatal Exposure Delayed Effects/immunology , Receptor, ErbB-4/immunology , Animals , Autistic Disorder/immunology , Behavior, Animal/physiology , Disease Models, Animal , Female , Fetus/metabolism , Gestational Age , Male , Memory, Short-Term , Mice , Mice, Inbred Strains , Neuregulin-1/genetics , Neuregulin-1/metabolism , Neuregulins/metabolism , Poly I-C/pharmacology , Pregnancy , Rats , Rats, Sprague-Dawley , Receptor, ErbB-4/metabolism , Receptors, Dopamine D2/immunology , Receptors, Dopamine D2/metabolism , Schizophrenia/immunology , Sex Factors , Signal Transduction/immunology
3.
Mol Psychiatry ; 23(11): 2227-2237, 2018 11.
Article in English | MEDLINE | ID: mdl-28727685

ABSTRACT

Genetic variants of Neuregulin 1 (NRG1) and its neuronal tyrosine kinase receptor ErbB4 are associated with risk for schizophrenia, a neurodevelopmental disorder characterized by excitatory/inhibitory imbalance and dopamine (DA) dysfunction. To date, most ErbB4 studies have focused on GABAergic interneurons in the hippocampus and neocortex, particularly fast-spiking parvalbumin-positive (PV+) basket cells. However, NRG has also been shown to modulate DA levels, suggesting a role for ErbB4 signaling in dopaminergic neuron function. Here we report that ErbB4 in midbrain DAergic axonal projections regulates extracellular DA levels and relevant behaviors. Mice lacking ErbB4 in tyrosine hydroxylase-positive (TH+) neurons, but not in PV+ GABAergic interneurons, exhibit different regional imbalances of basal DA levels and fail to increase DA in response to local NRG1 infusion into the dorsal hippocampus, medial prefrontal cortex and dorsal striatum measured by reverse microdialysis. Using Lund Human Mesencephalic (LUHMES) cells, we show that NRG/ErbB signaling increases extracellular DA levels, at least in part, by reducing DA transporter (DAT)-dependent uptake. Interestingly, TH-Cre;ErbB4f/f mice manifest deficits in learning, spatial and working memory-related behaviors, but not in numerous other behaviors altered in PV-Cre;ErbB4f/f mice. Importantly, microinjection of a Cre-inducible ErbB4 virus (AAV-ErbB4.DIO) into the mesencephalon of TH-Cre;ErbB4f/f mice, which selectively restores ErbB4 expression in DAergic neurons, rescues DA dysfunction and ameliorates behavioral deficits. Our results indicate that direct NRG/ErbB4 signaling in DAergic axonal projections modulates DA homeostasis, and that NRG/ErbB4 signaling in both GABAergic interneurons and DA neurons contribute to the modulation of behaviors relevant to psychiatric disorders.


Subject(s)
Memory, Short-Term/physiology , Receptor, ErbB-4/physiology , Spatial Memory/physiology , Animals , Axons/metabolism , Behavior, Animal/physiology , Dopamine/metabolism , Dopaminergic Neurons/metabolism , ErbB Receptors/metabolism , Gene Expression Regulation/genetics , Hippocampus/metabolism , Interneurons/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuregulin-1/metabolism , Parvalbumins/metabolism , Prefrontal Cortex/metabolism , Receptor, ErbB-4/genetics , Receptor, ErbB-4/metabolism , Signal Transduction/physiology , Spatial Behavior/physiology , Synapses/metabolism , gamma-Aminobutyric Acid/metabolism
4.
Mol Psychiatry ; 23(5): 1233-1243, 2018 05.
Article in English | MEDLINE | ID: mdl-28322273

ABSTRACT

Numerous genetic and functional studies implicate variants of Neuregulin-1 (NRG1) and its neuronal receptor ErbB4 in schizophrenia and many of its endophenotypes. Although the neurophysiological and behavioral phenotypes of NRG1 mutant mice have been investigated extensively, practically nothing is known about the function of NRG2, the closest NRG1 homolog. We found that NRG2 expression in the adult rodent brain does not overlap with NRG1 and is more extensive than originally reported, including expression in the striatum and medial prefrontal cortex (mPFC), and therefore generated NRG2 knockout mice (KO) to study its function. NRG2 KOs have higher extracellular dopamine levels in the dorsal striatum but lower levels in the mPFC; a pattern with similarities to dopamine dysbalance in schizophrenia. Like ErbB4 KO mice, NRG2 KOs performed abnormally in a battery of behavioral tasks relevant to psychiatric disorders. NRG2 KOs exhibit hyperactivity in a novelty-induced open field, deficits in prepulse inhibition, hypersensitivity to amphetamine, antisocial behaviors, reduced anxiety-like behavior in the elevated plus maze and deficits in the T-maze alteration reward test-a task dependent on hippocampal and mPFC function. Acute administration of clozapine rapidly increased extracellular dopamine levels in the mPFC and improved alternation T-maze performance. Similar to mice treated chronically with N-methyl-d-aspartate receptor (NMDAR) antagonists, we demonstrate that NMDAR synaptic currents in NRG2 KOs are augmented at hippocampal glutamatergic synapses and are more sensitive to ifenprodil, indicating an increased contribution of GluN2B-containing NMDARs. Our findings reveal a novel role for NRG2 in the modulation of behaviors with relevance to psychiatric disorders.


Subject(s)
Dopamine/metabolism , Mental Disorders/metabolism , Nerve Growth Factors/deficiency , Animals , Behavior, Animal/physiology , Brain/metabolism , Clozapine/pharmacology , Dopamine/genetics , ErbB Receptors/metabolism , Male , Mental Disorders/genetics , Mice , Mice, Knockout , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Neuregulin-1/genetics , Neuregulin-1/metabolism , Receptor, ErbB-4/genetics , Receptor, ErbB-4/metabolism , Signal Transduction , Synapses/metabolism , Transcriptome
6.
Gene ; 271(2): 285-91, 2001 Jun 27.
Article in English | MEDLINE | ID: mdl-11418250

ABSTRACT

The enzyme myo-inositol monophosphatase (Impa) catalyzes the synthesis of free myo-inositol from various myo-inositol monophosphates in the phosphatidylinositol signaling system. Impa is a lithium-blockable enzyme that has been hypothesized to be the biological target for lithium-salts used as mood-stabilizing drugs in the treatment of manic-depressive (bipolar) illness. As an initial step to explore the functional consequences of reduced or absent Impa activity in an animal model we here report the isolation of two Impa-encoding mouse genes, Impa1 and Impa2. Impa1 spans approximately 17.5 kb and contains nine exons of 46--1354 bp encoding a protein of 277 amino acids. Impa2 spans at least 19.5 kb and contains eight exons of 46--444 bp size encoding a protein of 290 amino acids. The genomic structure including the positions of the exon-intron splice sites seems to be conserved among myo-inositol monophosphatase genes in mammalian species. One or more Impa-like genes do also exist in evolutionary more distant species like invertebrates, plants and bacteria. The proteins encoded by the non-vertebrate genes seem to be equally related to Impa1 and Impa2. We therefore suggest that the Impa1 and Impa2 genes duplicated from a common ancestral gene after the evolutionary divergence of vertebrates.


Subject(s)
Genes/genetics , Phosphoric Monoester Hydrolases/genetics , Animals , Base Sequence , DNA/chemistry , DNA/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , Eukaryotic Cells/enzymology , Exons , Humans , Introns , Mice , Molecular Sequence Data , Prokaryotic Cells/enzymology , Sequence Analysis, DNA , Species Specificity
7.
World J Biol Psychiatry ; 2(2): 95-8, 2001 Apr.
Article in English | MEDLINE | ID: mdl-12587191

ABSTRACT

BACKGROUND: Inositol monophosphatase (IMPase) activity was reported to be low in lymphocyte-derived cell lines of bipolar patients. METHODS: IMPase activity was measured spectrophotometrically as inorganic phosphate liberated from inositol-1-phosphate. RESULTS: The previously reported reduction was replicated in a new, small group of bipolar patients. The reduction is not present in cell lines of unipolar or schizophrenic patients. IMPase activity in postmortem frontal and occipital cortical samples of unipolar, bipolar and schizophrenic patients was not different from controls. CONCLUSIONS: A reduction in lymphocyte-derived IMPase activity without a parallel reduction in cortical IMPase activity could be due to the fact that most leukocyte IMPase activity is the product of the IMPA-2 gene.


Subject(s)
Bipolar Disorder/enzymology , Bipolar Disorder/pathology , Brain/enzymology , Brain/pathology , Lymphocytes/pathology , Phosphoric Monoester Hydrolases/metabolism , Adult , Aged , Cell Culture Techniques , Enzyme-Linked Immunosorbent Assay , Female , Frontal Lobe/enzymology , Frontal Lobe/pathology , Humans , Male , Middle Aged , Occipital Lobe/enzymology , Occipital Lobe/pathology , Spectrophotometry
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