The impressive progress in brain research has produced a substantial gap between our detailed knowledge of the molecular and cellular interactions in the brain and the mental processes that these interactions give rise to. Our research tries to help bridge this gap by focusing on the systems-level physiology of the hippocampus. The aim is to learn how a neural system coordinates the activation of the momentarily relevant representations it has stored while suppressing the activation of momentarily irrelevant representations. Behavioral models of cognition, pharmacological, electrophysiological, and computational techniques are employed to understand how operations of the hippocampal system are related to the details of spatial behavior and its modulation by learning, attention, and stress. For example, by studying the information that rats use to navigate, we learned that they form multiple memories of places, and that these memories are organized in distinct spatial reference frames corresponding roughly, to the "room" and "floor" (Fenton et al., 1998). This is analogous to how people riding the bus understand where they are on the bus as well as where they are in the city. Using drugs to permanently or temporarily inactivate parts of the hippocampus, we found that without a functioning hippocampus, rats cannot coordinate the two representations of the room and the floor (Cimadevilla et al., 2001; Wesierska et al., 2005). This work used active place avoidance task variants that were developed as a sensitive set of assays for hippocampal dysfunction. We recently used the task to demonstrate that the same molecular mechanism (PKMzeta) that maintains LTP in the hippocampus also maintains hippocampus-dependent memory. Inhibiting PKMzeta activity in the hippocampus returned long-term (22-hr) potentiated synaptic transmission to baseline values and dramatically erased long-term (1 day-old) and remote (30 days-old) place avoidance memories (Pastalkova et al., 2006) without impairing baseline synaptic transmission or the ability to learn and remember a new place avoidance.

We also record the activity of ensembles of single hippocampal neurons that indicate the rat's current location. We interpret recordings of these "place cells" as a reflection of what the rat currently "knows" about its location. We showed that if rats learn to navigate a space, presumably attending to its features, this causes the network of place cell activity to organize into separate and conjunctive representations of the room and floor (Zinyuk et al., 2000). We noticed that place cells, which on the average represent the same locations, moment to moment have unpredictable and uncoordinated activity (Fenton and Muller, 1998). We hypothesized this was due to a selective attention-like control of their activity (Olypher et al., 2002) and subsequently we found that explicitly reinforcing the rat to represent locations in the room distinctly from locations on the floor, that place cell activity became temporally organized. Place cells representing the same locations now segregated into subsets that discharged together, subsets that discharged independently, and subsets that did not discharge together. We study this neural coordination of cognitive representations as a model for the cognitive coordination that may underlie thinking. We are investigating whether our recent discovery that altering neural coordination so hippocampal neurons that once weakly discharged together now more readily discharge together, can help explain thought disorders in people with psychosis. These people cannot readily separate relevant, irrelevant, inappropriate and unreal mental representations. We are trying to apply our insights into how spatial knowledge is organized in animals to understand whether mental disorders associated with schizophrenia, depression, Alzheimer's Disease, autism and epilepsy can be better understood in terms of a fundamental inability to effectively coordinate the activation and suppression of neural representations of experience and knowledge.

Selected Publications

Fenton, A. A., and Muller, R. U. (1998). Place cell discharge is extremely variable during individual passes of the rat through the firing field. Proc. Natl. Acad. Sci. USA 95, 3182-3187.

Fenton, A. A., Wesierska, M., Kaminsky, Y., and Bures, J. (1998). Both here and there: simultaneous expression of autonomous spatial memories. Proc. Natl. Acad. Sci. USA 95, 11493-11498.

Zinyuk, L., Kubik, S., Kaminsky, Y., Fenton, A.A. and Bures, J. (2000). Understanding hippocampal activity using purposeful behavior: Place navig ation induces place cell discharge in both the task-relevant and task-irrelevant spatial reference frames. Proc. Natl. Acad. Sci. USA 97, 3771-3776.

Fenton, A. A., Csizmadia, G, and Muller, R. U. (2000). Conjoint control of hippocampal place cell firing by two visual stimuli: I. The effects of moving the stimuli on firing field positions. J. Gen. Physiol. 116, 191-210.

Cimadevilla, J. M., Wesierska, M., Fenton, A. A., and Bures, J. (2001). Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation. Proc. Natl. Acad. Sci. USA 98, 3531-3536.

Olypher, A. V., Lansky, P., and Fenton, A. A. (2002). Properties of the extra-positional signal in hippocampal place cell discharge derived from the overdispersion in location-specific firing. Neurosci. 111, 553-656.

Wesierska, M., Dockery, C., and Fenton, A. A. (2005). Beyond memory, navigation and inhibition: Behavioural evidence for hippocampus-dependent cognitive coordination in the rat. J. Neurosci. 25, 2413-2419.

Kubik, S., and Fenton, A. A. (2005). Behavioral evidence that segregation and representation are dissociable hippocampal functions. J. Neurosci. 25, 9205-9212.

Olypher, A. V., Klement, D., and Fenton, A. A. (2006). Cognitive disorganization in hippocampus: a physiological model of the disorganization in psychosis. J. Neurosci. 26, 158-168.

Pastalkova, E., Serrano, P., Pinkhasova, D., Wallace, E., Fenton, A.. A., and Sacktor, T. C. (2006). Storage of spatial information by the maintenance mechanism of LTP. Science 313, 1141-1144.

List of Publications (Pub Med)

Personnel

Eduard Kelemen, M.Sc., Graduate Student
Hsin-Yi Kao, M.Sc., Graduate Student
Heekyung Lee, B.S., Graduate Student

Service Functions

Reviewer for neuroscience journals.
President, Bio-Signal Group Corporation.