Project Details
Description
ABSTRACT
The highest cognitive functions such as reasoning, planning, and decision-making, are all, directly or
indirectly, influenced by our past personal experiences, which are represented in hippocampal-cortical circuits
as episodic memories. Dysfunction of these circuits has been linked to the most prevalent and challenging
mental disorders of our time, ranging from dementia to anxiety, depression, and post-traumatic stress disorder.
Understanding the neurobiological mechanisms of episodic memory formation and retrieval are therefore
essential for the development of effective molecular and circuit-based therapies for such disorders. The current
project focuses on systems consolidation, a process which, through sustained interactions between
hippocampal and cortical circuits, leads to a lasting cortical representation of episodic memories. Based on
existing evidence, including our own published and pilot data, we posit a key role of activity-dependent
inflammatory signaling in discrete dorsohippocampal (DH) projections to the retrosplenial cortex (RSC) in
systems consolidation, including tagging, activation, and deactivation of the DH-RSC circuit. Aim 1 is designed
to determine the contributions of discrete DH-RSC projections to early tagging of RSC and sustained
inflammatory signaling in DH and RSC. Aim 2 will focus on the direct contribution of hippocampal Toll-like
receptors (Tlr) to memory consolidation and induction of TGFb1, and Aim 3 will examine the contribution of
TGFb to the cortical dependence of memories and deactivation of inflammatory signaling in the DH-RSC
circuit. These aims will be tested in mouse models of episodic-like memories by applying projection-specific
manipulations of the DH-RSC circuit, cell-specific genetic manipulations of Tlr9 and TGFb receptors, and by
monitoring circuit activity through virally expressed signaling reporters in vivo. We also plan to apply
quantitative molecular biologic and biochemical approaches that will enable us to determine the concentration-
dependent TGFb effects on gene expression patterns associated with activation and deactivation of the DH-
RSC circuit. We believe that advancing our understanding of neuronal inflammation in the organization of
memory circuits will advance our fundamental knowledge of systems consolidation. At the same time, we hope
that circuit-specific Tlr9/TGFb signaling will emerge as candidate target for therapies for neuropsychiatric
disorders rooted in episodic memory deficits.
Status | Active |
---|---|
Effective start/end date | 7/1/16 → 4/30/24 |
Funding
- NATIONAL INSTITUTE OF MENTAL HEALTH: $423,380.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $72,902.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $288,596.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $424,725.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $710,744.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $796,951.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $424,725.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $424,725.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $484,916.00
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