Funded Grants

Neuronal mechanisms of episodic memory

In humans, ample evidence supports the critical role of the hippocampus and associated structures in declarative (episodic and semantic) memories (Scoville and Milner, 1957; Tulving, 1972; Squire 1992; Eichenbaum, 2002). During episodic recall, the content of memory evolves internally without assistance from environmental cues (Tulving 1972; Squire, 1992). It has been conjectured that the recall process involves linking neuronal assemblies into temporal "phase sequences" (Hebb, 1949) but studying the neuronal mechanisms of episodic recall has remained elusive because of the difficulties in accessing the content of free recall in animals (Kahana, 1996; Howard et al., 2005; Süddendorf and Corballis, 1997). Some theorists suggest that episodic memory is strictly a human characteristic because recalling the content of episodes requires verbal communication (Tulving, 1972; Süddendorf and Corballis, 1997). This proposal challenges that claim and suggests to examine the presence of cell assembly sequences in the brain as a potential substrate of episodic memory in rats.

Most physiological studies in animals suggest that the hippocampal system serves spatial navigation (O'Keefe and Nadel, 1978). It has been tacitly assumed that 'place' cell sequences in the hippocampus (O'Keefe and Dostrovsky 1971) result from serially ordered environmental stimuli as the animal traverses through space (O'Keefe and Nadel, 1978). However, some recent observations are at odds with the view that hippocampal cells simply respond to sensory inputs conveyed by the entorhinal cortex (Hafting et al., 2005). For example, hippocampal neurons signaling selectively the future or past segments of travel have been reported (Wood et al., 2000; Frank et al 2000; Fertinteanu and Shapiro, 2003; Bower et al., 2005). The sequences of place cells at the seconds scale are replicated within single cycles of hippocampal theta oscillations, and the distance representations between place fields are reflected by the spike time differences at these short temporal scale (Skaggs et al., 1996; Dragoi and Buzsaki, 2006). Finally, the hippocampus is known to generate self-organized patterns during sleep and immobility and the temporal recruitment of neurons within these patterns is related to the assembly sequences during waking experience (Buzsaki, 1989; Wilson and McNaughton, 1994).

The environment-controlled and internally generated frameworks of assembly sequences have distinct predictions. Consider that the rat is "frozen" in space while the theta oscillation mechanism is maintained. According to the map-based navigation theory (O'Keefe and Nadel, 1978; Huxter et al., 2003; O'Keefe and Burgess, 2005; Hafting et al; 2005) hippocampal place cells and entorhinal grid cells that are explicitly anchored to specific constellation of landmarks of the environment should display sustained activity while neurons representing other spatial positions should remain tonically suppressed. In contrast, if assembly sequences are generated by internal mechanisms, hippocampal neurons are expected to display an ever-changing activity even when environmental inputs are fixed and body cues are kept stationary, as is the hypothesized case during recall of episodic information. The experiments of this proposal are designed to confront the above predictions by examining the activity of hippocampal and entorhinal neurons in a custom-designed hippocampal-dependent delayed alternation in which the environmental and body-derived cues are kept constant.