Traumatic events, particularly during early life, have far-reaching consequences including increasing an individual's vulnerability to depression and anxiety disorders. However, there is a paucity of information concerning the impact of early traumatic experiences on the development of neural circuitry, and its relation to adult vulnerability to neuropsychiatric disorders. Moreover, it is known that there is considerable heterogeneity in response to traumatic stress in relation to later development of neuropsychiatric disorders. In the US, 20-30% of individuals exposed to traumatizing events subsequently exhibit symptoms of posttraumatic stress disorder (PTSD). Nonetheless, the characteristics of neural circuitries associated with either risk or resilience to these disorders re unknown. Understanding these issues is now possible with the advent of a novel approach capable of imaging resting-state functional connectivity (RSFC) in awake animals. This advancement is unique in its noninvasiveness, whole-brain coverage and high sensitivity to neuroplasticity, and thus is ideal for studying the dynamic changes of neural circuitry across brain development and under selective perturbations. By utilizing this approach, we propose to investigate the impact of early trauma on the development of the neural circuits implicated in stress-induced disorders in an animal model. Specifically, with a longitudinal design in which traumatic stress is administered during juvenile, adolescence or adulthood, we will characterize the impact of early trauma on the developmental trajectories of the neural circuits of medial prefrontal cortex (mPFC), amygdala (AMYG) and hippocampus (HP). In addition, we will examine the difference in these circuits in animals exhibiting high vulnerability to developing PTSD-like behaviors. This vulnerability will be evaluated based on cut-off criteria of an established PTSD animal model. Our preliminary data showed that the neural circuits of mPFC, AMYG and HP are still immature during adolescence. We also demonstrated that trauma exposure can induce long-lasting effects on the same neural circuits in adult rats. Intriguingly, vulnerable rats showed much weaker RSFC strength within the mPFC-AMYG circuit compared to resilient rats, implying that RSFC may predict vulnerability to PTSD. Based on these pilot data, we plan to accomplish the research objectives by pursuing three specific aims.
In Aim 1, we will characterize the normal developmental trajectories of the neural circuits of mPFC, AMYG and HP.
In Aim 2, we will evaluate the impact of early trauma exposure on the developmental trajectories of these neural circuits.
In Aim 3 we will assess the neural substrate underlying the vulnerability to PTSD in an animal model. The proposed work is innovative, because it combines novel neuroimaging tools and behavioral measurement to investigate the development of critical neural circuits and their vulnerability to traumatic stress. The impact of this research is highly significant because understanding the role of early trauma in neuroplastic changes in the circuitries subserving mood and anxiety disorders is critical to earlier diagnosis and treatment of these disorders.

Public Health Relevance

Early adverse life experiences have been associated with long-lasting psychological consequences across the lifespan. However there are many critical gaps in our understanding of the neural mechanisms that may sub-serve these processes. The proposed research projects will have significant impact on expanding our understanding of the role of adverse early life events and its'impact on adult psychopathology. These studies will provide a potential circuitry-level biomarker for the identification of vulnerability to stress-relted disorders, and can help early diagnosis and treatment of dysfunctions induced by exposure to early stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH098003-02
Application #
8721617
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Vicentic, Aleksandra
Project Start
2013-05-15
Project End
2018-04-30
Budget Start
2013-09-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$346,628
Indirect Cost
$96,628
Name
Pennsylvania State University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Ma, Zilu; Ma, Yuncong; Zhang, Nanyin (2018) Development of brain-wide connectivity architecture in awake rats. Neuroimage 176:380-389
Ma, Zhiwei; Perez, Pablo; Ma, Zilu et al. (2018) Functional atlas of the awake rat brain: A neuroimaging study of rat brain specialization and integration. Neuroimage 170:95-112
Dopfel, David; Zhang, Nanyin (2018) Mapping stress networks using functional magnetic resonance imaging in awake animals. Neurobiol Stress 9:251-263
Ma, Zhiwei; Zhang, Nanyin (2018) Temporal transitions of spontaneous brain activity. Elife 7:
Hamilton, Christina; Ma, Yuncong; Zhang, Nanyin (2017) Global reduction of information exchange during anesthetic-induced unconsciousness. Brain Struct Funct 222:3205-3216
Smith, Jared B; Liang, Zhifeng; Watson, Glenn D R et al. (2017) Interhemispheric resting-state functional connectivity of the claustrum in the awake and anesthetized states. Brain Struct Funct 222:2041-2058
Ma, Yuncong; Hamilton, Christina; Zhang, Nanyin (2017) Dynamic Connectivity Patterns in Conscious and Unconscious Brain. Brain Connect 7:1-12
Ma, Zhiwei; Zhang, Nanyin (2017) Cross-population myelination covariance of human cerebral cortex. Hum Brain Mapp 38:4730-4743
Lee, Athene K W; Gansler, David A; Zhang, Nanyin et al. (2017) Relationship of mindful awareness to neural processing of angry faces and impact of mindfulness training: A pilot investigation. Psychiatry Res Neuroimaging 264:22-28
Gao, Yu-Rong; Ma, Yuncong; Zhang, Qingguang et al. (2017) Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal. Neuroimage 153:382-398

Showing the most recent 10 out of 20 publications