The hippocampal-prefrontal circuit is implicated in many neuropsychiatric illnesses. This circuit is critically involved in multiple aspects of cognition and emotional regulation, and is particularly vulnerable to stress, which is a key precipitating factor for many of these disorders. Chronic stress can have deleterious effects on neuronal structure and physiological function in the hippocampus, and impair hippocampal-dependent behavior, including processing of contextual fear memories. The hippocampus and prefrontal cortex communicate during cognitive and emotional tasks by altering the coherence of oscillatory activity between the two regions. However, the cellular and molecular events that drive these changes in hippocampal-prefrontal synchrony, and how they are influenced by stress, are not well understood. Understanding the mechanisms by which exposure to stress leads to disruptions in hippocampal-prefrontal interactions during fear regulation is a high priority given that altered fear-related behavior is prominent in many neuropsychiatric disorders. Our preliminary data support the hypothesis that exposure to stress impacts plasticity in the hippocampal-prefrontal pathway, leading to disrupted connectivity between the two regions and enhanced fear-related behavior. Many of the risk factors for neuropsychiatric disorders, including stress, affect genes that play important roles in the development and plasticity of synapses. Hence, disruptions in synaptic connections of the long-range projections between the hippocampus and prefrontal cortex could contribute to impairments in hippocampal-prefrontal synchrony. However, there is a dearth of research aimed at understanding molecular signaling pathways in these projection cells. The central hypothesis of this proposal is that defined programs of cellular and molecular signaling in hippocampal-prefrontal projection neurons control their structure and function, and that these signaling pathways regulate patterns of neural activity and connectivity between the two structures. The overall goals of this application are to 1) understand how stress drives molecular and cellular signaling in hippocampal-prefrontal projection cells to control their physiological function; and 2) determine how plasticity in hippocampal-prefrontal projections neurons impacts functional connectivity in this circuit to control fear-related behavior. We use a technically sophisticated combination of neuronal morphology analysis with endoscopic imaging and in vivo electrophysiology to understand how stress impacts cellular plasticity in hippocampal-prefrontal projection neurons. We then determine how these cellular correlates of plasticity impact hippocampal-prefrontal synchrony during fear-related behavior. In addition to cellular correlates, we combine molecular profiling techniques with retrograde viral approaches to investigate molecular contributions to plasticity in hippocampal-prefrontal neurons. The research will reveal fundamental information about molecular and cellular signaling programs in hippocampal-prefrontal projection neurons that contribute to functional connectivity, information that will be critical for future strategies targeting this pathway.

Public Health Relevance

This hippocampal-prefrontal circuit is critically involved in multiple aspects of cognition related to executive function and emotional regulation, and implicated in a diverse array of brain disorders and neuropsychiatric illnesses. In this proposal we investigate the cellular and molecular signaling pathways that govern connectivity in this circuit. This proposal is relevant to the part of the NIH mission that pertains to the translation of basic mechanisms causing neurodevelopmental disorders and mental illnesses into innovative treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH105592-07
Application #
10088473
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Vicentic, Aleksandra
Project Start
2015-06-01
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Lieber Institute, Inc.
Department
Type
DUNS #
963044529
City
Baltimore
State
MD
Country
United States
Zip Code
21205
McAllan, Liam; Maynard, Kristen R; Kardian, Alisha S et al. (2018) Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice. Am J Physiol Endocrinol Metab :
Maynard, Kristen R; Hobbs, John W; Rajpurohit, Sumita K et al. (2018) Electroconvulsive seizures influence dendritic spine morphology and BDNF expression in a neuroendocrine model of depression. Brain Stimul 11:856-859
Hill, Julia L; Jimenez, Dennisse V; Mai, Yishan et al. (2018) Cortistatin-expressing interneurons require TrkB signaling to suppress neural hyper-excitability. Brain Struct Funct :
Maynard, Kristen R; Hobbs, John W; Phan, BaDoi N et al. (2018) BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior. Elife 7:
Maynard, Kristen R; Hobbs, John W; Sukumar, Mahima et al. (2017) Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus. Brain Struct Funct 222:3295-3307
Song, M; Martinowich, K; Lee, F S (2017) BDNF at the synapse: why location matters. Mol Psychiatry 22:1370-1375
Hill, J L; Hardy, N F; Jimenez, D V et al. (2016) Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation. Transl Psychiatry 6:e873
Hill, Julia L; Martinowich, Keri (2016) Activity-dependent signaling: influence on plasticity in circuits controlling fear-related behavior. Curr Opin Neurobiol 36:59-65
Maynard, Kristen R; Hill, Julia L; Calcaterra, Nicholas E et al. (2016) Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling. Neuropsychopharmacology 41:1943-55