By controlling the activity of cortex, the basal ganglia is critical to the organization of motor commands. However, how information about the context in which a movement is executed is communicated to the basal ganglia is poorly understood. In particular, connections between stress activated nuclei in the hypothalamus, amygdala, and bed nucleus of the stria terminalis (BST) that respond to threats in the environment, and the basal ganglia are poorly characterized. This proposal uses the expression and localization of the stress neuropeptide, Corticotropin Releasing Factor (CRF), and its primary receptor, CRFR1 to uncover how stress signals reach the basal ganglia. Within the basal ganglia, CRFR1 is highly expressed by a subset of neurons in the external Globus Pallidus (GPe). In preliminary experiments, we traced the inputs to CRFR1 neurons in the GPe and found novel connections from CRF neurons in stress responsive nuclei. We hypothesize that previously unmapped circuits from these nuclei coordinate stress-induced movement via the GPe. In this proposal, we will test this hypothesis using three parallel strategies. First, we aim to map the connectivity of CRF-rich, stress responsive nuclei with the GPe using monosynaptic rabies viral tracing, direct immuno?uorescence, and optogenetics assisted circuit mapping. Then, we will test the functional impact of CRF on the properties of synaptic connections between these nuclei. Finally, we will activate or inhibit particular pathways and assay resulting anxiety-related behavior to determine how the GPe acts to bias movement in stress-relevant contexts. The experiments proposed will probe the anatomy, physiology, and function of the robust, but poorly described connection between limbic circuits that respond to stress and basal ganglia circuits that pattern movement.

Public Health Relevance

Stress and anxiety can profoundly impact our ability to move, which is critical to our daily existence. In many cases of depression and anxiety-related disease, as well as in neurodegenerative diseases such as Parkinson's disease, the ability to move is impaired, a symptom that is severely exacerbated by high levels of stress. In this proposal we aim to uncover how neural circuits that are activated by stress interface with motor circuits that pattern movement to understand how varying degrees of stress in?uence the circuits that ultimately control our ability to move.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH112768-01A1
Application #
9398512
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Simmons, Janine M
Project Start
2017-06-05
Project End
2022-03-31
Budget Start
2017-06-05
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$480,317
Indirect Cost
$114,579
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Jiang, Zhiying; Rajamanickam, Shivakumar; Justice, Nicholas J (2018) Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus. J Neurosci 38:1874-1890
Justice, Nicholas J (2018) The relationship between stress and Alzheimer's disease. Neurobiol Stress 8:127-133
Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698