The hippocampus (HPC) is required for spatial representations and new episodic memories, while the medial prefrontal cortex (mPFC) is critical for outcome and reward associations, and consequent decision making. Previous studies have found communication from HPC to mPFC during hippocampal sharp wave-ripples (SWRs), neural events with increased coordinated activity. My long-term research goal is to understand how activity in neural circuits gives rise to complex behaviors, and how these circuits and behaviors are altered in pathological states. In this proposal, we consider activity during awake SWRs in hippocampal subfield CA1, the output region of the hippocampus, the anterior cingulate cortex (ACC), and prelimbic cortex (PLC), subdivisions of mPFC whose activity can reflect reward and other outcome information. While it is known that activity in the hippocampus during SWRs can decode to predictive trajectories from an animal's current location to a future goal location, and that awake SWRs are important for memory-guided task performance, numerous gaps in our understanding remain. First, the specific role of awake SWRs in supporting behavior remains unknown. Second, previous studies have not established if activity in mPFC during awake SWRs is causally related to SWRs. Third, although it has been hypothesized that awake SWR-associated mPFC activity represents reward outcome predictions of planned actions, this remains unsubstantiated. We hypothesize that awake SWRs are the neural substrate of information flow of planned spatial trajectories from HPC to mPFC, necessary for consequent evaluation of related outcomes and memory-guided decision making. To address this possible role in decision making, we will use multi-electrode implants to record neural activity in CA1 and mPFC of rats engaged in a memory-guided task (Aims 1, 2, and 3). We will also use a bipolar stimulating electrode in the ventral hippocampal commissure for electrophysiological manipulation to establish causal roles of awake SWRs in prefrontal activity patterns (Aim 2) and decision making (Aim 3).
Our specific aims are:
Specific Aim 1 : To test the hypothesis that mPFC activity corresponding to awake SWRs can represent outcomes of planned trajectories.
Specific Aim 2 : To test the hypothesis that awake SWRs drive changes in mPFC activity related to decision making.
Specific Aim 3 : To test the hypothesis that awake SWRs are necessary for decision making. Accomplishing these Specific Aims will reveal the functional role of awake SWRs as a neural substrate for retrieval and information transfer between structures. This research is necessary for understanding the origins and consequences of hippocampal-prefrontal dysfunction, as encountered in the range of neuropsychiatric disorders linked to the both structures. These disorders include schizophrenia, mood disorders, post-traumatic stress disorder, autism spectrum disorders, and dementia.

Public Health Relevance

The hippocampus and prefrontal cortex are brain structures critical to our ability to remember facts, places, and events, as well as to deliberate between options. Dysfunction of the hippocampus and prefrontal cortex are associated with age-related memory loss, autism spectrum disorders, schizophrenia, depression, and addiction - yet we do not understand how interaction between these two structures contributes to the complex behavioral changes observed in these disorders. The proposed research will help us better understand the normal information transfer between the hippocampus and prefrontal cortex, specifically by interrupting and characterizing memory replay events, sharp wave-ripples, during times of decision making, and may thus provide the basis for more effective treatments of disorders involving the hippocampus and prefrontal cortex.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Van'T Veer, Ashlee V
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Chung, Jason E; Magland, Jeremy F; Barnett, Alex H et al. (2017) A Fully Automated Approach to Spike Sorting. Neuron 95:1381-1394.e6