Extinction-induced "despair" in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus.

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.

Decreased proliferation in the adult rat hippocampus after exposure to the Morris water maze and its reversal by fluoxetine.

Granular cell proliferation in the adult hippocampus decreases during aging and after chronic stress, while it can be increased by physical activity or treatment with the antidepressant fluoxetine. We investigated whether the physical and cognitive stimulation accompanied by stress in the commonly used Morris water maze affects the rate of proliferation and whether the induced changes can be influenced by antidepressant treatment with fluoxetine. Proliferating cells in the dentate gyrus were labeled by three injections of BrdU during the 24h preceding sacrifice. Early differentiation to neuronal progeny was studied by immunohistochemical staining for doublecortin (DCX), a microtubule binding protein expressed in newborn neurons. Acquisition learning in the water maze for 15 days caused a significant decrease in granular cell proliferation in the granular cell layer of the hippocampus. The decrease in the number of BrdU- and DCX-positive cells was reversed to control levels by the use of fluoxetine during the water maze training. Fluoxetine treatment alone increased the number of BrdU-positive cells, but did not increase the number of DCX-positive cells. We conclude that the exposure of adult male rats to water maze acquisition trials is a stressful experience that significantly suppresses the production of new granular cells and that this stressful effect can be blocked by the concomitant administration of the antidepressant fluoxetine.

Metabolite and diffusion changes in the rat brain after Leksell Gamma Knife irradiation.

Our study describes the time course of necrotic damage to the rat brain resulting from Leksell Gamma Knife (LGK) irradiation at a dose that was previously considered to be subnecrotic. A lesion induced in the rat hippocampus by 35 Gy irradiation was monitored by MRI, MRS, and DW-MRI for 16 months. T2-weighted images revealed a large hyperintense area with an increased apparent diffusion coefficient of water (ADCw), which occurred 8 months after irradiation, accompanied by metabolic changes (increase of lactate (Lac) and choline (Cho), and decrease of creatine (Cr) and N-acetyl aspartate (NAA), as determined by MRS) that indicated an edema. In two animals, the hyperintensity persisted and a postnecrotic cavity connected to enlarged lateral ventricles developed. In the rest of the animals, the hyperintensity started to decrease 9 months post-irradiation (PI), revealing hypointense areas with a decreased ADCw. Histology confirmed the MRI data, showing either scar formation or the development of a postnecrotic cavity.

Mice with astrocyte-directed inactivation of connexin43 exhibit increased exploratory behaviour, impaired motor capacities, and changes in brain acetylcholine levels.

Gap junctions mediate communication between many cell types in the brain. Gap junction channels are composed of membrane-spanning connexin (Cx) proteins, allowing the cell-to-cell passage of small ions and metabolites. Cx43 is the main constituent of the brain-spanning astrocytic gap junctional network, controlling activity-related changes in ion and glutamate concentrations as well as metabolic processes. In astrocytes, deletion of Cx43-coding DNA led to attenuated gap junctional coupling and impaired propagation of calcium waves, known to influence neuronal activity. Investigation of the role of Cx43 in behaviour has been impossible so far, due to postnatal lethality of its general deletion. Recently, we have shown that deletion of Cx30, which is also expressed by astrocytes, affects exploration, emotionality, and neurochemistry in the mouse. In the present study, we investigated the effects of the astrocyte-directed inactivation of Cx43 on mouse behaviour and brain neurochemistry. Deletion of Cx43 in astrocytes increased exploratory activity without influencing habituation. In the open field, but not in the elevated plus-maze, an anxiolytic-like effect was observed. Rotarod performance was initially impaired, but reached control level after further training. In the water maze, Cx43 deficient mice showed a steeper learning course, although final performance was similar between groups. Cx43 inactivation in astrocytes increased acetylcholine content in the frontal cortex of water maze-trained animals. Results are discussed in terms of altered communication between astrocytes and neurons, possible compensation processes, and differential effects of Cx30- and astrocyte-specific Cx43 deletion.

Leksell gamma knife lesioning of the rat hippocampus: the relationship between radiation dose and functional and structural damage.

OBJECT: The goals of the study were to determine at what dosage and after what interval impairment of hippocampal function occurs after Leksell gamma knife radiosurgery (GKS) of the rat hippocampus and to assess the associated structural changes. METHODS: Long-Evans rats were irradiated with maximum doses of 25, 50, 75, 100, and 150 Gy, and four 4-mm isocenters were used to cover the hippocampus bilaterally. The impairment of hippocampal function, which is associated with a loss of memory, was measured by testing the impairment of the rats' orientation in a Morris water maze. Changes in the irradiated tissue were measured using magnetic resonance imaging (Bruker 4.7/20 experimental spectrometer). The data were compared with histologically demonstrated changes. Significantly higher incidences of edema, necrosis, and behavioral changes were observed following administration of doses higher than 50 Gy. No edema, necrosis, or behavioral changes were observed when doses were 25 Gy. CONCLUSIONS: It would seem that rats can be used for experiments involving the induction of complex brain lesions by using four 4-mm isocenters. Testing retention memory for behavioral changes after bilateral GKS of the whole hippocampus proved insensitive; acquisition memory should be tested to assess functional changes of hippocampus. Significantly higher incidences of edema, necrosis, and behavioral changes were observed for doses higher than 50 Gy. There seems to be a therapeutic window during which doses may affect epilepsy without impairing the memory of the rat.