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Positron emission tomography (PET) neuroimaging and behavioral assays in rodents are widely used in neuroscience. PET gives insights into the molecular processes of neuronal communication, and behavioral methods analyze the actions that are associated with such processes. These methods have not been directly integrated, because PET studies in animals have until now required general anesthesia to immobilize the subject, which precludes behavioral studies. We present a method for imaging awake, behaving rats with PET that allows the simultaneous study of behavior. Key components include the 'rat conscious animal PET' or RatCAP, a miniature portable PET scanner that is mounted on the rat's head, a mobility system that allows considerable freedom of movement, radiotracer administration techniques and methods for quantifying behavior and correlating the two data sets. The simultaneity of the PET and behavioral data provides a multidimensional tool for studying the functions of different brain regions and their molecular constituents. [ABSTRACT FROM AUTHOR]

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) of Parkinson’s disease (PD) are of growing diagnostic and therapeutic importance. Data on their prevalence and characteristics have been primarily derived from highly selective clinical populations. We have conducted a national study in the outpatient care sector to provide a fuller characterization of the frequency of dementia, depression, and other NPS in PD outpatients. We also examined associations with biosocial and neurological variables. A nationwide representative sample of 1,449 PD outpatients was examined with a standardized clinical interview. PD severity was rated with the Hoehn and Yahr (HY) scale and the Unified Parkinson’s Disease Rating Scale. Depression was measured with the Montgomery-Asberg Depression Rating Scale. Cognitive impairment and dementia were assessed with the Mini-Mental State Exam and according to diagnostic criteria. Logistic regression analyses were used to investigate associations. At least one NPS occurred in 71% of all patients with PD. The estimated prevalences (ranges) by age group and HY-stage were: depression, 25% (13.2–47.9%), dementia, 29% (12.2–59.4%), and psychotic syndromes, 12.7% (3.1–40.9%). Other frequent complications were sleep disturbances (49%) and anxiety (20%). Depression was associated with gender but not with age. Dementia was associated with age. The rates and comorbidity of depression and dementia were driven by PD severity. NPS were highly prevalent in our comprehensive patient sample, largely representative of management problems occurring in an outpatient setting. PD outpatients are at an increased risk for all neuropsychiatric conditions, increasing with PD severity but not with age or age of onset (except dementia), revealing challenging symptom patterns. [ABSTRACT FROM AUTHOR]

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 ( NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples. [ABSTRACT FROM AUTHOR]

The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations ( P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation. [ABSTRACT FROM AUTHOR]

Despite considerable public interest research in neurobiological correlates of pedophilia is scarce. Since amygdala activation is central for emotional valuation, arousal, and salience, we investigated the activation profile of this structure in 10 male subjects with pedophilia (exclusively attracted to boys), all convicted sex-offenders and sentenced to forensic psychiatric treatment along with ten male heterosexual matched controls. We used a sexually non-explicit functional Magnetic Resonance Imaging (fMRI) paradigm with images of men, women, boys or girls randomly embedded in neutral target/non-target geometrical symbols. We applied statistical parametric mapping (SPM2) and SPSS 14 for image processing and analysis. While controls activated significantly less to pictures of children compared to adults, the activation profile was reversed in subjects with pedophilia, who exhibited significantly more activation to children than adults. The highest activation was observed for boys in the patient group, and for women in control participants. Our data show enhanced activation to children’s pictures even in an incidental context and suggest the provocative hypothesis that a normally present mechanism for reduced emotional arousal for children relative to adults is reversed in pedophilia, suggesting a neural substrate associated with deviant sexual preference in this condition. More extensive research in this field would be of benefit for both the victims and the offenders. [ABSTRACT FROM AUTHOR]

There is growing evidence that stress causes a decrease of neurogenesis in the dentate gyrus and antidepressant treatment in turn stimulates the cell proliferation in the dentate gyrus. This has led to the hypothesis that a decreased neurogenesis might be linked to the pathophysiology of major depression. The article reviews the relationship of depressive-like behavior and neurogenesis in three animal models of depression with high validity: learned helplessness, chronic mild stress and chronic psychosocial stress of the tree shrew. All animal models provide evidence that stress which can lead to depressive-like behavior, in parallel causes a decrease of neurogenesis; vice versa, antidepressant treatment is able to revert not only behavioral changes but also to normalize neurogenesis. But the animal models argue against the notion that decreases of neurogenesis are the cause or the consequence of depressive-like behavior since depressive-like behavior can occur without impairments in neurogenesis and decreasing neurogenesis does not neccessarily lead to depressive-like behavior. This suggests that neurogenesis does not directly control affect but is tightly connected to the modulation of affect by stress and antidepressant measures. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine whether MR-detectable alterations of choline-containing compounds in two key neural systems involved in major depression disorder namely the hippocampus and the basal ganglia can be detected. Multislice proton magnetic resonance spectroscopic imaging was applied in 11 patients with major depressive disorder (MDD) and ten matched healthy subjects. Voxels were selected from the left and right side of the hippocampus and the putamen. Significantly lower choline-containing compounds in the hippocampus and significantly higher choline-containing compounds in the putamen of patients with MDD compared to healthy subjects were found. No significant differences were found for the other metabolites in the two regions evaluated. Abnormal levels of choline-containing compounds most likely reflect altered membrane phospholipid metabolism. A reduced level in the hippocampus and an increased level in the putamen suggest regionally opponent membrane abnormalities. [ABSTRACT FROM AUTHOR]

Disturbance of synaptic transmission is currently viewed as an important pathophysiological mechanism and therapeutic target of mood disorders. Amongst other lines of evidence this theory is based on human postmortem investigations showing differential expression of complexins. In order to discriminate between molecular correlates of the disease itself and effects of psychotropic drugs given to patients, we performed an animal trial using subchronic antidepressant treatment. Cohorts of adult male Sprague--Dawley rats were treated over a period of 14 days with intraperitoneal injections of either saline (0.9%, n=8), desipramine (15 mg/kg, n=7), fluoxetine (10 mg/kg, n=8), or tranylcypromine (10 mg/kg, n=5). Brain slices were used for in situ hybridizations with 35S labelled RNA probes of the genes complexin I, complexin II and syntaxin 1 A, the SNARE complex protein interacting with the complexins, and assessed semi-quantitatively for regionspecific expression levels. Expression of complexin I was induced only in habenular nuclei after treatment with fluoxetine. In contrast, complexin II was significantly induced by desipramine and tranylcypromine, but not fluoxetine, in several brain regions. All treatment groups, but most significantly fluoxetine-treated animals, showed higher expression levels of syntaxin 1A. Antidepressants differentially affect expression levels of complexin I and more prominently complexin II and syntaxin 1A. The induction of complexin II and syntaxin 1A might strengthen the synaptic transmission at axo-dendritic or axo-axonal synapses. Previous post-mortem findings reporting on downregulation of complexins cannot be explained as mere effects of psychotropic drug treatment. [ABSTRACT FROM AUTHOR]

Discusses a study which investigated a voluntary alcohol intake in two rat lines selectively bred for learned helpless and non-helpless behavior. Background of studies on the comorbidity of alcoholism and depressive disorders; Relationship between high alcohol intake and a depressed-like state in alcohol-preferring rat lines; Results of sucrose preference test; Alcohol self-administration procedure.

In order to develop a model for a depression-like syndrome in mice, we subjected male CS7BL/6 mice to a 4-week-long chronic stress procedure, consisting of rat exposure, restraint stress, and tail suspension. This protocol resulted in a strong decrease in sucrose preference, a putative indicator of anhedonia in rodents. Interestingly, predisposition for stress-induced anhedonia was indicated by submissive behavior in a resident-intruder test. In contrast, most mice with nonsubmissive behavior did not develop a decrease in sucrose preference and were regarded as nonanhedonic. These animals were used as an internal control for stress-induced behavioral features not associated with the anhedonic state, since they were exposed to the same stressors as the anhedonic mice. Using a battery of behavioral tests after termination of the stress procedure, we found that anhedonia, but not chronic stress per se, is associated with key analogues of depressive symptoms, such as increased floating during forced swimming and decreased exploration of novelty. On the other hand, increased anxiety, altered locomotor activity, and loss of body weight were consequences of chronic stress, which occurred independently from anhedonia. Thus, behavioral correlates of stress-induced anhedonia and of chronic stress alone can be separated in the present model. [ABSTRACT FROM AUTHOR]

Background: The hippocampus, thalamus and basal ganglia are among the brain regions of major interest in schizophrenia. Aims: The purpose of this study was to corroborate previous findings of reduced N-acetylaspartate in the hippocampal and thalamic regions and to investigate possible metabolite changes in the putamen in schizophrenia. Method: MRSI study of the thalamus, basal ganglia, and hippocampus in 13 schizophrenic patients under stable medication and age-matched healthy controls. Results A decrease of the N-acetylaspartate signal was found in the hippocampal region and the thalamus but not in the putamen of patients compared to controls. No significant group differences in the signals from creatine and phosphocreatine, and choline-containing compounds were found in the hippocampal region and the putamen but the signal from choline-containing compounds was decreased in the thalamus of patients. Conclusion: Metabolic processes in the basal ganglia of schizophrenic patients seem to be opposite the hippocampal and thalamus findings. [ABSTRACT FROM AUTHOR]

Studies the effects of long-term antipsychotic treatment on N-methyl-D-aspartate (NMDA) receptor binding and gene expression of subunits. Treatment of male Sprague-Dawley rats with haloperidol and clozapine; Effects on NMDA receptor binding in animal model; Mechanisms of action and comparison with post-mortem studies in schizophrenia.

Positron emission tomography (PET) and the deoxyglucose method were used to measure cerebral metabolism in 14 normals and 13 schizophrenics at rest and during performance of simple and complex finger-movement sequences. The normals, but not the schizophrenics, showed significant metabolic activation in mesial frontal and contralateral sensorimotor and premotor regions during the complex movement. The relative metabolism of schizophrenics was significantly lower than normal in frontal regions and higher than normal in thalamus and basal ganglia under all scanning conditions. The results suggest that schizophrenics may have a brain dysfunction which limits their capacity to produce a focal metabolic response to stimulation in several functionally distinct brain regions. [ABSTRACT FROM AUTHOR]

A technique for obtaining glial plasma membrane has been developed, starting with a bulk-prepared glial cell-enriched fraction from rabbit cerebral cortex. The astrocytic-enriched fraction was hand-homogenized in isotonic sucrose media, and the crude membrane fraction sedimented at 3,000 g. The isolation of a membrane-enriched fraction was accomplished with sucrose density gradient centrifugation. The plasma membrane fraction was collected at the interphase between 31.5% and 25.5% sucrose. Enzymatic and electron-microscopical analyses indicated a 4-7-fold enrichment in plasma membrane, and a 15-20% contamination with microsomal and mitochondrial material. Some multilaminar membrane structures were also seen in the fraction. [ABSTRACT FROM AUTHOR]

In recent years the illicit drug ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) has come into widespread use among young people. Despite clear evidence for the neurotoxic potential of MDMA in animals, corresponding evidence in humans is limited to indirect findings. In an exploratory study we compared the hippocampal [sup 1] H-MRSI (magnetic resonance spectroscopic imaging) spectra of five MDMA users with those of controls with no history of substance abuse. Although [sup 1] H-MRSI is sensitive in detecting alterations in neuronal viability in association with diseases leading to neuronal degeneration, we were not able to demonstrate any differences in hippocampal [sup 1] H-MRSI between MDMA users and controls. [ABSTRACT FROM AUTHOR]

The article reports on the potential role of the thalamus and lateral habenula for deep brain stimulation in depression. It explains that lateral habenula controls the midbrain monoaminergic nuclei and carries information from the amygdala related to anxiety and from the medial prefrontal cortex (mPFC) related to depression. It adds that over activation of the habenula which is driven by the mPFC, allows mediation of a depressive state development by altered monoaminergic function.