Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats.

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion.

Proteomic analysis identifies alterations in cellular morphology and cell death pathways in mouse brain after chronic corticosterone treatment.

Some patients with Major Depression and other neurological afflictions display hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. HPA hyperactivity may be due to impaired feedback inhibition and manifested as increased levels of circulating cortisol. Subcutaneous implants of corticosterone pellets were used to mimic this situation in mice to gain insight into any effects on brain function by comparative proteomic analysis using two-dimensional Differential In-Gel Electrophoresis. A total of 150 different protein spots were altered by corticosterone treatment in the hypothalamus, hippocampus and cerebral cortex. Of these, 117 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass fingerprinting equating to 51 different proteins. Association of these corticosterone-modulated proteins with biological functions using the Ingenuity Pathways Analysis tool showed that cell morphology was significantly altered in the hippocampus and cerebral cortex, whereas the hypothalamus showed significant changes in cell death. Ingenuity Pathways Analysis of the canonical signaling pathways showed that glycolysis and gluconeogenesis were altered in the hypothalamus and the hippocampus and all three brain regions showed changes in phenylalanine, glutamate and nitrogen metabolism. Further elucidation of these pathways could lead to identification of biomarkers for the development of pharmacological therapies targeted at neuropsychiatric disorders.

A goal direction signal in the human entorhinal/subicular region.

Navigating to a safe place, such as a home or nest, is a fundamental behavior for all complex animals. Determining the direction to such goals is a crucial first step in navigation. Surprisingly, little is known about how or where in the brain this "goal direction signal" is represented. In mammals, "head-direction cells" are thought to support this process, but despite 30 years of research, no evidence for a goal direction representation has been reported. Here, we used fMRI to record neural activity while participants made goal direction judgments based on a previously learned virtual environment. We applied multivoxel pattern analysis to these data and found that the human entorhinal/subicular region contains a neural representation of intended goal direction. Furthermore, the neural pattern expressed for a given goal direction matched the pattern expressed when simply facing that same direction. This suggests the existence of a shared neural representation of both goal and facing direction. We argue that this reflects a mechanism based on head-direction populations that simulate future goal directions during route planning. Our data further revealed that the strength of direction information predicts performance. Finally, we found a dissociation between this geocentric information in the entorhinal/subicular region and egocentric direction information in the precuneus.