Christine Winter

A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.

Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders.

Prenatal viral infection has been associated with development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) administration of influenza virus. We hypothesized that late second trimester infection (E18) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6J mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offsping of the infected mice were collected at P0, P14, P35 and P56, their brains removed and prefrontal cortex, hippocampus and cerebellum dissected and flash frozen. Microarray, qRT-PCR, DTI and MRI scanning, western blotting and neurochemical analysis were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with schizophrenia or autism including Sema3a, Trfr2 and Vldlr were found to be altered as were protein levels of Foxp2. E18 infection of C57BL6J mice with a sublethal dose of human influenza virus led to significant gene alterations in frontal, hippocampal and cerebellar cortices of developing mouse progeny. Brain imaging revealed significant atrophy in several brain areas and white matter thinning in corpus callosum. Finally, neurochemical analysis revealed significantly altered levels of serotonin (P14, P35), 5-Hydroxyindoleacetic acid (P14) and taurine (P35). We propose that maternal infection in mouse provides an heuristic animal model for studying the environmental contributions to genesis of schizophrenia and autism, two important examples of neurodevelopmental disorders.

Enriched environment induces cellular plasticity in the adult substantia nigra and improves motor behavior function in the 6-OHDA rat model of Parkinson's disease

The adult substantia nigra bears the capacity to generate new neural cells throughout adulthood. The mechanisms of cellular plasticity in this brain region remain unknown. In the adult dentate gyrus, dopamine was suggested to be one of the key players in neurogenesis. We therefore investigated nigral cellular plasticity in the 6-OHDA rat model of Parkinsons disease. The absolute numbers of newborn cells in the SN were not affected by dopamine depletion. Interestingly, we found a specific downregulation of generation of newborn nigral astrocytic cells. As enriched environment with physical activity are robust inducers of neuro- and gliogenesis in the adult DG, we investigated the role of these physiological stimuli in nigral cellular plasticity and in motor behavior of 6-OHDA lesioned rats. We describe a significant increase in numbers of newborn NG2-positive and GFAP-positive cells in the SN. Moreover, 6-OHDA lesioned animals living in enriched environment with physical activity for 7 weeks showed improved motor behavior compared to controls under standard conditions. Thus, physiological neurogenic and gliogenic stimuli induce significant microenvironmental changes in the adult SN and improve motor behavior in the 6-OHDA lesion model of PD.

The effects of electrode material, charge density and stimulation duration on the safety of high-frequency stimulation of the subthalamic nucleus in rats

High-frequency stimulation (HFS) of deep brain structures is a powerful therapeutic tool for the treatment of various movement disorders in patients. However, the pathophysiological mechanisms of this therapeutic approach on basal ganglia network function are still largely unknown. Hitherto, experimental studies have focused on short-term stimulation. Since patients receive HFS for many years, animal studies which reproduce the conditions of long-term stimulation will be necessary to accurately investigate the effects of HFS. However, stimulation parameters of acute HFS cannot be easily transferred to long-term conditions. Accordingly, for this purpose we studied the influence of different charge densities (0, 3, 6.5, 13 and 26 microC/cm2/phase) and duration (4 h or 3 days) of subthalamic nucleus (STN)-HFS using stainless-steel and platinum-iridium (Pt/Ir) electrodes on neuronal tissue damage in rats. Our data demonstrate the advantage of Pt/Ir over stainless-steel electrodes when used in short-term HFS (frequency 130 Hz, pulse width 60 micros) and indicate that HFS using Pt/Ir-electrodes pulsed with 3 microC/cm2/phase over 3 days did not produce any relevant tissue damage in the STN.

Phenotypic differences in behavior, physiology and neurochemistry between rats selected for tameness and for defensive aggression towards humans

To better understand the biology of tameness, i.e. tolerance of human presence and handling, we analyzed two lines of wild-derived rats (Rattus norvegicus) artificially selected for tameness and defensive aggression towards humans. In response to a gloved human hand, tame rats tolerated handling, whereas aggressive rats attacked. Cross-fostering showed that these behavioral differences are not caused by postnatal maternal effects. Tame rats were more active and explorative and exhibited fewer anxiety-related behaviors. They also had smaller adrenal glands, larger spleens and lower levels of serum corticosterone. Blood glucose levels were lower in tame rats, whereas the concentrations of nine amino acids were higher. In the brain, tame rats had lower serotonin and higher taurine levels than aggressive rats. Our findings reinforce the notion that tameness is correlated with differences in stress response and will facilitate future efforts to uncover the genetic basis for animal tameness.

Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats

Depression is the most common psychiatric complication in Parkinsons disease (PD). The pathophysiological events leading to PD-associated depression, however, remain largely unknown. The present study tested the differential implication of dopaminergic systems in depressive-like behavior in rats and its response to l-Dopa and the selective serotonin reuptake inhibitor citalopram. The learned helplessness model was used as a behavioral paradigm. Rats were lesioned in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) and assigned to subgroups with respect to the stereologically verified extent of the nigral and/or VTA degeneration. Both lesions increased depressive-like behavior in rats, which was reduced by both citalopram and l-Dopa treatment. We conclude that dopaminergic lesions of either the SNc or the VTA contribute to the manifestation of depressive-like behavior in rats. The effects of citalopram administration on depressive behavior induced by lesions of dopaminergic brain regions furthermore suggest an involvement of serotonergic pathways in dopaminergic cell loss-induced depression.

Dopamine and serotonin levels following prenatal viral infection in mouse : Implications for psychiatric disorders such as schizophrenia and autism

Prenatal viral infection has been associated with neurodevelopmental disorders such as schizophrenia and autism. It has previously been demonstrated that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and middle-late second trimester (E18) administration of influenza virus. Neurochemical analysis following infection on E18 using this model has revealed significantly altered levels of serotonin, 5-hydroxyindoleacetic acid, and taurine, but not dopamine. In order to monitor these different patterns of monoamine expression in exposed offspring in more detail and to see if there are changes in the dopamine system at another time point, pregnant C57BL6J mice were infected with a sublethal dose of human influenza virus or sham-infected using vehicle solution on E16. Male offspring of the infected mice were collected at P0, P14, and P56, their brains removed and cerebellum dissected and flash frozen. Dopamine and serotonin levels were then measured using HPLC-ED technique. When compared to controls, there was a significant decrease in serotonin levels in the cerebella of offspring of virally exposed mice at P14. No differences in levels of dopamine were observed in exposed and control mice, although there was a significant decrease in dopamine at P14 and P56 when compared to P0. The present study shows that the serotonergic system is disrupted following prenatal viral infection, potentially modelling disruptions that occur in patients with schizophrenia and autism.

High frequency stimulation and temporary inactivation of the subthalamic nucleus reduce quinpirole-induced compulsive checking behavior in rats

Obsessive-compulsive disorder (OCD) represents a highly prevalent and impairing psychiatric disorder. Functional and structural imaging studies implicate the involvement of basal ganglia-thalamo-cortical circuits in the pathophysiology of this disorder. In patients remaining resistant to pharmaco- and behavioral therapy, modulation of these circuits may consequently reverse clinical symptoms. High frequency stimulation (HFS) of the subthalamic nucleus (STN), an important station of the basal ganglia-thalamo-cortical circuits, has been reported to reduce obsessive-compulsive symptoms in a few Parkinsons disease patients with comorbid OCD. The present study tested the effects of bilateral HFS of the STN and of bilateral pharmacological inactivation of the STN (via intracranial administration of the GABA agonist muscimol) on checking behavior in the quinpirole rat model of OCD. We demonstrate that both HFS and pharmacological inactivation of the STN reduce quinpirole-induced compulsive checking behavior. We conclude that functional inhibition of the STN can alleviate compulsive checking, and suggest the STN as a potential target structure for HFS in the treatment of OCD.

High-frequency stimulation of the nucleus accumbens core and shell reduces quinpirole-induced compulsive checking in rats

Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy‐refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti‐compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD‐like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole‐induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.

High frequency stimulation and pharmacological inactivation of the subthalamic nucleus reduces ‘compulsive’ lever-pressing in rats

In recent years there have been several attempts to establish high frequency stimulation (HFS) as an additional treatment strategy for obsessive-compulsive disorder (OCD). Two studies reported that bilateral HFS of the subthalamic nucleus (STN) dramatically alleviated compulsions and improved obsessions in three patients with co-morbid Parkinsons disease and OCD. A recent study reported that HFS as well as pharmacological inactivation of the STN alleviate compulsive checking in the quinpirole rat model of OCD. As the quinpirole model is based on a dopaminergic manipulation, the aim of the present study was to test whether HFS and pharmacological inactivation of the STN exert an anti-compulsive effect also in the drug-naive brain, using the signal attenuation rat model of OCD. The main finding of the present study is that both HFS and pharmacological inactivation of the STN exerted an anti-compulsive effect, although the two manipulations differed in their effects on other behavioral measures. These findings support the possibility that HFS of the STN may provide an additional therapeutic strategy for OCD.