Chronic stress has been implicated in depression, anxiety disorders, and various cognitive deficits. The underlying mechanisms are poorly understood but are thought to involve dendritic spine loss in limbic brain areas mediated in part by prolonged exposure to glucocorticoids. These hormones are released from the adrenal gland in response to stress, and they also oscillate in synchrony with the circadian rhythm. Recently, we have shown that glucocorticoids have rapid and potent effects on dendritic spine remodeling in superficial cortex. Still, very little is known about how stress affects this dynamic remodeling process in limbic areas or whether circadian glucocorticoid oscillations play any specific role in regulating it. How stress-induced changes in spines may relate to changes in functional connectivity in limbic circuitry is also unknown. The central hypothesis of this project is that circadian glucocorticoid oscillations regulate synaptic remodeling in limbic circuits by generating and stabilizing new spines, and that chronic stress leads to dysregulated remodeling and circuit dysfunction by disrupting these oscillations. Experiments to be conducted during the mentored phase will focus on the rapid effects of oscillating levels of glucocorticoid activity.
Aim 1 will evaluate rapid effects on dendritic spine formation and elimination in infralimbic cortex using time-lapse microendoscopy, a recently developed tool for in vivo imaging of deep brain structures.
Aim 2 will test for corresponding on functional connectivity, using optogenetic tools t stimulate amygdala projections to infralimbic cortex while measuring evoked activity using optrode recordings and functional magnetic resonance imaging. Research during the independent phase (Aim 3) will build on these results by evaluating the chronic effects of prolonged glucocorticoid exposure on spine remodeling, functional connectivity, and anxiety. In the process, the candidate will become proficient in the use of the tools described above, leveraging prior experience with similar methods. This will be accomplished under the supervision of a team of mentors and consultants (Deisseroth, Schatzberg. Raichle, de Lecea, Barretto) who pioneered these methods and have extensive experience training others to use them. They also have highly successful track records in preparing junior investigators for the transition to independence. We anticipate that this project will yield novel insights regarding the importance of circadian oscillations in glucocorticoid activity, particularly for stabilizing dendrtic spines and preserving connectivity within limbic circuits. The results will also inform future efforts to study stress and glucocorticoid effects on functional connectivity in healthy human subjects and clinical populations.

Public Health Relevance

Chronic stress may precipitate problems with mood, anxiety, and cognition. These symptoms are thought to arise as a consequence of prolonged exposure to glucocorticoid stress hormones. Coincidentally, synthetic glucocorticoids are also mainstays of treatment for a variety of neurological and autoimmune diseases, but these treatments have been linked to cognitive side effects and effects on mood that are poorly understood. The main objective of this project is to advance our understanding of how glucocorticoid stress hormones regulate connectivity and function in brain circuits that play a central role in multiple neuropsychiatric diseases. The long-term goal is to inform future studies aimed at treating and prevent these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Career Transition Award (K99)
Project #
1K99MH097822-01
Application #
8353522
Study Section
Special Emphasis Panel (ZMH1-ERB-L (03))
Program Officer
Desmond, Nancy L
Project Start
2012-08-15
Project End
2014-07-31
Budget Start
2012-08-15
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$104,742
Indirect Cost
$7,759
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Avissar, Michael; Powell, Fon; Ilieva, Irena et al. (2017) Functional connectivity of the left DLPFC to striatum predicts treatment response of depression to TMS. Brain Stimul 10:919-925
Dubin, Marc J; Mao, Xiangling; Banerjee, Samprit et al. (2016) Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy. J Psychiatry Neurosci 41:E37-45
Pattwell, Siobhan S; Liston, Conor; Jing, Deqiang et al. (2016) Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. Nat Commun 7:11475
Lan, Martin J; Chhetry, Binod Thapa; Liston, Conor et al. (2016) Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex Induces Brain Morphological Changes in Regions Associated with a Treatment Resistant Major Depressive Episode: An Exploratory Analysis. Brain Stimul 9:577-83
Liston, Conor; Chen, Ashley C; Zebley, Benjamin D et al. (2014) Default mode network mechanisms of transcranial magnetic stimulation in depression. Biol Psychiatry 76:517-26
Liston, Conor; Cichon, Joseph M; Jeanneteau, Freddy et al. (2013) Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Nat Neurosci 16:698-705