The hippocampus has a critical role in several fundamental memory operations, including the conditioning of fear to contextual information. We show that the hippocampus is necessary also for unconditioned fear, and that the involved circuitry is at the ventral pole of the hippocampus. Rats with selective hippocampal lesions failed to avoid open arms in an elevated plus-maze and had decreased neuroendocrine stress responses during confinement to a brightly lit chamber. These effects were reproduced by lesions of the ventral half of the hippocampus, but not by damage to the dorsal three-quarters of the hippocampus or the amygdala. Ventral lesions failed to impair contextual fear conditioning or spatial navigation, suggesting that the ventral hippocampus may specifically influence some types of defensive fear-related behavior.defensive ͉ rat ͉ plus-maze ͉ water maze ͉ corticosterone T he experience of anxiety and fear is controlled by a modular neural system including regions in the brainstem, hypothalamus, and deeper parts of the temporal lobe (1-4). The amygdala plays a pivotal role in this system. It controls a broad range of fear reactions, and exhibits neural plasticity that may permit fear responses to be conditioned to new types of experience (refs. 1-5; but see ref. 6). Conditioned fear depends strongly on the basolateral complex of the amygdala (the lateral, basolateral, and basomedial nuclei), whereas the central nucleus and the bed nucleus of the stria terminalis are thought to be the principal output structures, mediating fear-related signals to behavioral, autonomic, and endocrine response systems in the hypothalamus and brainstem (1-5).Conditioning of fear to multimodal stimuli such as context and spatial location also requires the integrity of the hippocampus (7-9). The hippocampus is strongly involved in the encoding of spatial and episodic memories (10-12), and contextual fear conditioning is thought to require many of the associative algorithms responsible for these types of memory (13)(14)(15). Although the hippocampal influence on fear reactions may be a necessary consequence of its mnemonic operations, it is also possible that the hippocampus controls fear and anxiety independently of learning (16). This view is based particularly on the similar effects that anxiolytic drugs and septal-hippocampal lesions have on behavior in aversively motivated tasks. However, except for early studies showing that rats with large nonselective hippocampal lesions exhibit reduced food neophobia (17)(18)(19) and reduced freezing in the presence of a predator (20), direct evidence is absent. We now show (i) that the hippocampus controls defensive fear responses during exposure to a potentially threatening environment, (ii) that the relevant circuitry is located at the ventral pole of the hippocampus, and (iii) that this circuit may be dissociable from the associative circuits involved in contextual fear conditioning. Methods Subjects.A total of 187 male Long Evans rats (250-450 g) were housed individually in tran...

Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca2+ ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK−/−). MCAO was performed in BK−/− and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK−/− mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK−/− vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK−/− mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK−/− than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage.

The biology of glioblastoma invasion and its mechanisms are poorly understood. We demonstrate using time-lapse microscopy that grafting of glioblastoma (GBM) tumorspheres into rodent brain slices results in experimental ex vivo tumors with invasive properties that recapitulate the invasion observed after orthotopic transplantation into the rodent brain. The migratory movements and mitotic patterns were clearly modified by signals extrinsic to the invading cells. The cells migrated away from the tumorspheres, and removal of the spheres reduced the directed invasive movement. The cell cultures contained different populations of invasive cells that had distinct morphology and invasive behavior patterns. Grafts of the most invasive GBM culture contained 91±8% cells with an invasive phenotype, characterized by small soma with a distinct leading process. Conversely, the majority of cells in less invasive GBM grafts were phenotypically heterogeneous: only 6.3±4.1% of the cells had the invasive phenotype. Grafts of highly and moderately invasive cultures had different proportions of cells that advanced into the brain slice parenchyma during the observation period: 89.2±2.2% and 23.1±6.8%, respectively. In grafts with moderately invasive properties, most of the cells (76.8±6.8%) invading the surrounding brain tissue returned to the tumor bulk or stopped centrifugal migration. Our data suggest that the invasion of individual GBM tumors can be conditioned by the prevalence of a cell fraction with particular invasive morphology and by signaling between the tumor core and invasive cells. These findings can be important for the development of new therapeutic strategies that target the invasive GBM cells.

It has been proposed that the hippocampus exerts a tonic inhibitory influence on the hypothalamic-pituitary-adrenal (HPA) stress axis. This claim rests, in particular, on the upregulation of corticosterone secretion and other measures of HPA activity after nonselective lesions of the hippocampal formation. We measured plasma corticosterone concentrations after selective neurotoxic damage to the hippocampus and the subiculum in rats. Concentrations were estimated during rest in the rat's home cage and at several time points after varying degrees of stress. Lesions of the hippocampus did not increase the concentration of corticosterone relative to control rats in any condition. Temporary inactivation of the hippocampus or the ventral subiculum by infusion of the GABA A receptor agonist muscimol also failed to induce hypersecretion, although hippocampal infusions did impair spatial memory. These results suggest that the hippocampus is not necessary for tonic inhibition of adrenocortical activity and imply that the HPA axis receives efficient negative feedback inhibition from other brain systems too.

Purpose To investigate prediction of age older than 18 years in sub-adults using tooth tissue volumes from MRI segmentation of the entire 1st and 2nd molars, and to establish a model for combining information from two different molars. Materials and methods We acquired T2 weighted MRIs of 99 volunteers with a 1.5-T scanner. Segmentation was performed using SliceOmatic (Tomovision©). Linear regression was used to analyse the association between mathematical transformation outcomes of tissue volumes, age, and sex. Performance of different outcomes and tooth combinations were assessed based on the p-value of the age variable, common, or separate for each sex, depending on the selected model. The predictive probability of being older than 18 years was obtained by a Bayesian approach using information from the 1st and 2nd molars both separately and combined. Results 1st molars from 87 participants, and 2nd molars from 93 participants were included. The age range was 14-24 years with a median age of 18 years. The transformation outcome (high signal soft tissue + low signal soft tissue)/total had the strongest statistical association with age for the lower right 1st (p= 7.1*10-4 for males) and 2nd molar (p=9.44×10-7 for males and p=7.4×10-10 for females). Combining the lower right 1st and 2nd molar in males did not increase the prediction performance compared to using the best tooth alone. Conclusion MRI segmentation of the lower right 1st and 2nd molar might prove useful in the prediction of age older than 18 years in sub-adults. We provided a statistical framework to combine the information from two molars.

Purpose Our aim was to investigate tissue volumes measured by MRI segmentation of the entire 3rd molar for prediction of a sub-adult being older than 18 years. Material and method We used a 1.5-T MR scanner with a customized high-resolution single T2 sequence acquisition with 0.37 mm iso-voxels. Two dental cotton rolls drawn with water stabilized the bite and delineated teeth from oral air. Segmentation of the different tooth tissue volumes was performed using SliceOmatic (Tomovision©). Linear regression was used to analyze the association between mathematical transformation outcomes of the tissue volumes, age, and sex. Performance of different transformation outcomes and tooth combinations were assessed based on the p value of the age variable, combined or separated for each sex depending on the selected model. The predictive probability of being older than 18 years was obtained by a Bayesian approach. Results We included 67 volunteers (F/M: 45/22), range 14–24 years, median age 18 years. The transformation outcome (pulp + predentine)/total volume for upper 3rd molars had the strongest association with age (p = 3.4 × 10−9). Conclusion MRI segmentation of tooth tissue volumes might prove useful in the prediction of age older than 18 years in sub-adults.