Proposal Summary
The long-term goal of this research training plan is to enhance our understanding of the neurobiology underlying
behavioral responses to danger signals and provide translatable findings that will contribute to the development of novel
therapeutics and treatments for anxiety-related disorders. This research proposal was crafted to build a foundation for
becoming a fully independent scientist through developing technical expertise in systems neuroscience techniques,
increasing my knowledge base, learning programming and data analysis skills, and refining my professional development
skills. Boston College was selected as the environment for me to carry out this proposal and achieve my training goals due
to its accessible and expert behavioral neuroscience faculty, wide range of available techniques and equipment, and access
to the large neuroscience network within the greater Boston area. The research objective is to identify and describe a
dorsal raphe nucleus (DRN) to insula tract responsible for responding to danger signals and executing appropriate
behavioral responses in males and females. Hyperactivity of the DRN and effects of 5-HT released in the forebrain are
closely related to anxiety-related behaviors. Similarly, the insula integrates interoceptive and exteroceptive cues and
contributes to motivated behaviors that are influenced by anxiety. Although both the DRN and insula have been
implicated separately in anxiety-related behaviors, it is not yet known how 5-HT influences this system. The aims of this
proposal are designed to describe how insular 5-HT modulates the appropriate behavioral responses to danger signals.
Aim 1 will utilize a viral-genetic anterograde tracing method to describe and compare insular DRN projections and
serotonergic receptors colocalizations between insular rostral-caudal subregions, insular subregions, and laminar layers. It
is expected that DRN projections will target both inhibitory and excitatory neurons in all insula subregions and colocalize
on 5-HT2C receptors expressing neurons in the insula. Aim 2 will next seek to visualize insular serotonergic activity in
response to a social and directly experienced danger cue using GRAB5-HT, a sensor for 5-HT activity, and in vivo fiber
photometry. It is expected that there will be greater insular 5-HT activity in response to a stressed conspecific and danger
cue than a naive conspecific and safety cue, respectively. Finally, Aim 3 uses a chemogenetic approach to inhibit or
stimulate insula-projecting DRN neurons to determine if the DRN-insula tract is necessary and sufficient for the
appropriate behavioral response to a social and directly experienced danger cue. Inhibiting the DRN-insula tract should
increase sociability while decreasing fear, while stimulating the DRN-insula tract should trigger 5-HT release, therefore
decreasing sociability but increasing fear. Completion of these three complementary aims will result in the most thorough
understanding of this circuitry’s composition and function in response to danger signals to date and inform development
of more effective treatments for anxiety-related disorders.