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.
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.
| 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 |
