Memory for autobiographic events (episodic memory, EM) requires hippocampal function, but its neural correlates are unknown. In rats, an analogous process referred to as episodic-like memory can be used to devise behavioral tasks suitable for recording hippocampal activity. We previously found that when rats perform a + maze task with episodic-like memory aspects, most of the spatially selective activity of CA1 hippocampal neurons encodes origin and destination of journeys. This type of activity, referred to as hippocampal journey-dependent coding (HJDC), is modulated when the demand for hippocampal-dependent memory changes. HJDC forms therefore temporally extended representations that could contribute to EM. To demonstrate a direct link between HJDC and EM, experimental manipulation of HJDC in relevant memory tasks is necessary. This approach is currently not possible because the mechanisms generating HJDC are not known. Our long-term goal is to identify the neurophysiological substrates of EM. The objective of the current proposal, which is the first step in attaining the long-term goal, is to understand how spatially-selective CA1 activity becomes journey-dependent and thus how experimental manipulation of HJDC might be possible. Our central hypothesis is that HJDC is generated by a combination of input from the entorhinal cortex (EC) with input from CA3 hippocampal neurons. The rationale underlying the proposed research is that if mechanisms generating HJDC are understood and procedures can be devised to allow its selective experimental manipulation in behaviorally relevant experiments, the neural underpinning of EM can be identified. This hypothesis will be tested by pursuing two specific aims: 1. Assess the role of EC and CA3 activity in performance of a + maze spatial navigation task with serial reversals we previously used to record HJDC;and 2. Characterize simultaneously recorded CA1, EC and CA3 activity in normal animals and compare it with activity in remaining areas after EC or CA3 lesions in rats performing the +maze spatial navigation task. Under the first aim, we will identify the behavioral deficits following ECor CA3 neurotoxic lesions in the hippocampal-dependent task previously used and compare with performance in a hippocampal-independent task similar in overt behavior. These lesions, which we have shown are feasible in our hands, will target 1)EC input to all hippocampal fields;2) EC input to CA1 and subiculum only;and 3) CA3 input to CA1. Under the second aim, we will first record CA1, CA3, and EC activity in normal animals and then compare it to activity recorded after either of the three types of lesions described above. The approach is innovative because it involves high density hippocampal recording in a behavioral paradigm whose neurobiological substrate will be well understood. The proposed research is significant because unless we understand how HJDC is generated in CA1, we cannot manipulate it experimentally to establish its behavioral relevance. In turn, without such knowledge, we cannot develop treatments for memory disorders that would target specific neural processes.
The proposed research is relevant to public health because understanding the neurophysiological substrate of memory is a critical step in developing treatments for memory disorders such as Alzheimer's disease, or rehabilitation procedures following brain injury that affect memory. Thus, the proposed research is relevant to the NIMH mission that pertains to understanding when, where, and how to intervene in the mental illnesses
| Ferbinteanu, Janina (2016) Contributions of Hippocampus and Striatum to Memory-Guided Behavior Depend on Past Experience. J Neurosci 36:6459-70 |
