Identifying and Defining a Neural Circuit Underlying Fear and Anxiety-Related Behaviors

• Applicant: Vivan Nguyen Chi, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Anatomy and Physiology ; Human Cognitive and Systems Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401040418

I 2015 it was estimated that about 43 million people between the age of 18 or older are affected - worldwide, Steel et al. summarized that around 18% of the population meets the criteria for psychiatric disorders, the lifetime prevalence was estimated to almost 30% worldwide. Psychiatric disorders are widely associated with dysfunctions in the brain circuitry. Current therapies such as benzodiazepines and selective serotonin reuptake inhibitors remain ineffective in a large portion of affected individuals. However, the underlying circuits and how their dysfunction leads to disease remain elusive. Indeed either hypo- or hyperactivation of some circuits may lead to certain neuropsychiatric diseases. One such illness, Post-traumatic stress disorder (PTSD) characterized by an overgeneralization of fear to innocuous events as a consequence of a previously traumatic experience. This leads to heightened, physiological responses to stimuli that resemble the original traumatic stimuli, leading to maladaptive fear and avoidance behavior. One potential neural substrate for the overgeneralization of fear is the hippocampus, which has been shown to be reduced in volume in individuals suffering from PTSD. Dysfunction in hippocampal circuit may lead to not only deficits in memory and cognitive related processes, but also in the emotional responses to fearful stimuli. The ventral portion of the hippocampus (vHPC) is of particular interest, as it participates in regulating emotion and anxiety-like behaviors. The vHPC sends direct projections to a number of downstream limbic targets such as the amygdala, bed nucleus stria terminalis (BNST) and hypothalamus, which may mediate the overgeneralized fear response seen in individuals who develop PTSD. However, it remains unknown how dysfunction in hippocampal-limbic circuitry and the memory traces stored within them may lead to maladaptive behavior and disease states. I will focus in this proposed project on the ventral hippocampus (vHPC) of which circuits disrupted in anxiety-related disorders remain largely unknown. Thus, I propose to establish a functional anatomical activity-dependent connectivity matrix of the vHPC-subcortical interactions, as well as to determine whether unconditioned stimuli are encoded and represented within the vHPC population. To achieve these goals, I will use fluorescently labeled neuronal retrograde viral tracers to map out the activity-dependent recruited neuron assemblies and their downstream projection targets after application of unconditioned stimuli. I will also deliver a calcium-sensitive indicator to vHPC principal neurons to measure their population activity for the unconditioned stimulus and determine whether these encode and represent normal adaptive behaviors in the vHPC. Hence, identifying these neural circuits that mediate normal adaptive fear and avoidance behaviors will elucidate the underlying mechanisms and generation of anxiety-related disorders.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Mazen Kheirbek, Ph.D.