Amnesia is a debilitating condition that burdens not only the affected individual but their loved ones as well. In order to develop effective treatments for amnesia, the neural mechanism underlying long term memory storage, or consolidation, needs to be understood. Several theories exist regarding memory consolidation. One such theory, called the standard consolidation theory (SCT), posits that memories are initially retained in hippocampal-cortical networks which are then gradually distributed to cortico-cortical networks as a more permanent form of storage. Behavioral lesion studies using the trace eyeblink conditioning (EBC) paradigm have provided support for SCT, showing dorsal hippocampal (HP) functioning is essential for acquisition but not retention of the paradigm, whereas medial prefrontal cortex (mPFC) functioning is critical for retention but not acquisition of the paradigm. Despite these findings that conform to SCT, electrophysiological evidence in support of SCT remains scarce. Only a handful of studies have examined dorsal HP or mPFC single neuron activity during trace EBC but none have examined activity from both of these regions simultaneously within the same subject over a time frame that examines both recently and remotely acquired trace EBC. In addition, tracing studies show no monosynaptic connections that directly link the dorsal HP to the mPFC. Thus, it remains unclear 1) whether the firing patterns of dorsal HP and mPFC neurons conform to SCT in a time-dependent manner and 2) how dorsal HP memory traces are ?transferred? to the mPFC via consolidation as suggested by SCT. Recent anatomical tracing studies have shown that the dorsal HP may communicate with the mPFC via the anterior thalamus (AT), suggesting a dorsal hippocampal-anterior thalamic-medial prefrontal (dHP-AT-mPFC) circuit may be responsible for the consolidation of trace EBC. Our proposed research aims to first, investigate the firing characteristics of neurons within the dHP-AT-mPFC circuit and whether they support SCT (aim 1), then aims to elucidate the functional role of the AT in trace EBC (aim 2). Specifically, we will simultaneously record single neuron activity from the dorsal HP, AT, and mPFC within the same subjects as they undergo trace EBC acquisition and retention training. In accordance with SCT, we hypothesize dorsal HP and AT neurons will exhibit robust activity during acquisition, whereas mPFC neurons will exhibit greater activity during retention sessions. Preliminary results demonstrate a greater involvement of AT during acquisition of trace EBC, suggesting its role as a ?relay? that transfers HP memory traces to the mPFC. We will further test this premise by observing the effects of temporally precise optogenetic inactivation of AT nuclei on behavioral performance during trace EBC acquisition and retention. We hypothesize that inactivation of AT will result in impaired retention of trace EBC but not acquisition by ?blocking? the transfer of HP memory traces to the mPFC. Results may provide electrophysiological evidence in support or in opposition of SCT and further provide insight into the role of the dHP-AT-mPFC circuit in trace EBC and memory consolidation.

Public Health Relevance

Amnesia associated with dementia and cognitive disorders like Alzheimer's disease is a debilitating condition that not only burdens the affected individual but the individual's loved ones and the health care system as well. Our current understanding of human memory - how it is constituted and how it falters - remains riddled with assumptions and conjectures, thus making development of treatments and cures for amnesia difficult. This proposal, which aims to investigate the neurophysiological basis of memory formation, storage, and retrieval in the hippocampus, thalamus, and medial prefrontal cortex, will enhance our understanding of how the brain enables memory processes and thus may serve as a foundation for the development of new treatments for memory impairments.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH099769-02
Application #
8718808
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rosemond, Erica K
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hattori, Shoai; Yoon, Taejib; Disterhoft, John F et al. (2014) Functional reorganization of a prefrontal cortical network mediating consolidation of trace eyeblink conditioning. J Neurosci 34:1432-45