Project Summary
Episodic memory describes our ability to weave temporally contiguous elements into recollections of
rich and coherent experiences. Episodic memory formation is specifically degraded by degenerative
conditions such as Alzheimer’s Disease. The activity of ‘time cells’ in the mesial temporal lobe may
provide a mechanism for the coding of temporal information that is necessary for the formation of these
memories, and we recently published evidence of time cells in the human hippocampus using
microelectrode recordings from epilepsy patients. The spike rate of these cells reliably increases at
specific moments within a fixed interval, and groups (assemblies) of time cells can represent a ‘temporal
space’ analogous to the manner in which hippocampal place cells are held to represent physical space,
imposing temporal organization on event representations. In this proposal, we build on preliminary
data to investigate the flexible participation of time cells in neuronal assemblies using established
methods. We will test how time cells support serial memory by adjudicating between two models, one
based on time cell activity (`time cell model’) versus a different proposed mechanism by which serial
recall depends on the consistent phase offset of the spiking of hippocampal neurons relative to theta
oscillations (‘phase offset model’). This experiment will test key unresolved questions about how time
cells contribute to episodic memory. Finally, we will test the impact of cholinergic blockade on time
cells and cell assemblies. This novel experiment builds on the preliminary data we present in our
proposal showing the effects of scopolamine administration in 10 intracranial EEG subjects, which
identify alterations in hippocampal theta and gamma oscillations in the setting of cholinergic blockade.
Our experiments include a number of key innovations, including examining time cell activity during serial
recall, assembly formation, and especially in the setting of modulation of cholinergic innervation. The
data we propose to collect will fill key gaps in understanding related to time cell activity in humans and
potentially establish cholinergic modulation in human intracranial EEG subjects as a method to elucidate
physiological patterns during mnemonic processing and to model the effects of disorders such as
Alzheimer’s Disease in this population.
