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Hippocampal firing is organized in theta sequences controlled by internal memory processes and by external sensory cues, but how these computations are coordinated is not fully understood. Although theta activity is commonly studied as a unique coherent oscillation, it is the result of complex interactions between different rhythm generators. Here, by separating hippocampal theta activity in three different current generators, we found epochs with variable theta frequency and phase coupling, suggesting flexible interactions between theta generators. We found that epochs of highly synchronized theta rhythmicity preferentially occurred during behavioral tasks requiring coordination between internal memory representations and incoming sensory information. In addition, we found that gamma oscillations were associated with specific theta generators and the strength of theta-gamma coupling predicted the synchronization between theta generators. We propose a mechanism for segregating or integrating hippocampal computations based on the flexible coordination of different theta frameworks to accommodate the cognitive needs.

Introduction and development. During episodes of ischemia/anoxia, the neurochemical and environmental changes considered toxic for nervous tissue lie behind the characteristic abrupt massive cell depolarization (MCD). A strong resemblance with otherpathologic events enable us to postulate thatMCD is a different state of the tissue that includes among others the anoxic depolarization and Leao's spreading depression. MCD is an active event. Neurons enter and leave MCD suddenly and synchronously, and contrary to current belief, their membrane integrity is preserved and ion gradients are only reduced. Biophysical membrane properties are not compatible with some postulates based on endotoxines. There is a direct relation between MCD susceptibility of the different neuron types/nuclei and their vulnerability to ischemia/anoxia. Two different substates can be distinguished in the associated interstitial potentials that are likely related to neuronal and glial dysfunction, respectively. The different modes and timings of anoxic neuronal death depend on the duration of MCD, the functional integrity of the glial network and the history ofprevious insults. Conclusions. MCD is a cellular state of risk bridging life and death. Neurons die if they cannot exit, but may recover if they do promptly, although still have to face subtle changes -as well initiated during MCD- that will eventually lead them to a delayed death. A voiding MCD is escaping death. From a clinical point of view, the relevant point is that manipulating MCD entails the simultaneous control of all 'toxic' neurochemical concomitants. Reinforcing vulnerable neurons to avoid their falling into MCD is possible.

If oxygen is withdrawn from rat hippocampal slices, a spreading depression-like response occurs earlier and is of larger amplitude in the CA1 area than in the dentate gyrus. After reoxygenation, recovery of synaptic transmission correlates inversely with the time spent in spreading depression. Recovery occurs more frequently in dentate gyrus than in CA1. Chlorpromazine and the gangliosides GM1 and AGF2 promote recovery from hypoxic depression of synaptic transmission in CA1. Prevention of irreversible loss of function correlates closely with a shortening of the time spent in spreading depression. If Ca2+ is withdrawn before hypoxia, then synaptic function recovers upon restoration of oxygen and [Ca2+]o, despite prolonged spreading depression. When spreading depression lasting more than 6-9 minutes is induced in fully oxygenated slices by superfusion with high-K+ solution, then transient recovery is followed by long-lasting loss of synaptic function. In intact brain of anesthetized rats, synaptic transmission in CA1 recovers after spreading depression-like depolarization lasting more than 30 minutes, but is lost irreversibly after 60 minutes. We conclude that entry of Ca2+ into neurons caused by spreading depression-like depolarization is important in the selective vulnerability of neurons; the duration of depolarization is critical to cell survival; and in the presence of a normal blood supply, neurons resist protracted spreading depression-like depolarization.

During episodes of ischemia/anoxia, the neurochemical and environmental changes considered toxic for nervous tissue lie behind the characteristic abrupt massive cell depolarization (MCD). A strong resemblance with other pathologic events enable us to postulate that MCD is a different state of the tissue that includes among others the anoxic depolarization and Le o s spreading depression. MCD is an active event. Neurons enter and leave MCD suddenly and synchronously, and contrary to current belief, their membrane integrity is preserved and ion gradients are only reduced. Biophysical membrane properties are not compatible with some postulates based on endotoxines. There is a direct relation between MCD susceptibility of the different neuron types/nuclei and their vulnerability to ischemia/anoxia. Two different substates can be distinguished in the associated interstitial potentials that are likely related to neuronal and glial dysfunction, respectively. The different modes and timings of anoxic neuronal death depend on the duration of MCD, the functional integrity of the glial network, and the history of previous insults.MCD is a cellular state of risk bridging life and death. Neurons die if they cannot exit, but may recover if they do promptly, although still have to face subtle changes as well initiated during MCD that will eventually lead them to a delayed death. Avoiding MCD is escaping death. From a clinical point of view, the relevant point is that manipulating MCD entails the simultaneous control of all toxic neurochemical concomitants. Reinforcing vulnerable neurons to avoid their falling into MCD is possible