Functional role of the cuneiform nucleus and its projections to the dorsolateral periaqueductal gray in defensive behaviors

• Grant number: 24/10023-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: October 01, 2024
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Newton Sabino Canteras
• Grantee: Juliane Midori Ikebara
• Supervisor: Fabricio Hoffmann Martins do Monte
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Texas Health Science Center at Houston (UTHealth), United States
• Associated to the scholarship: 22/16318-9 - Anatomical and functional study of the gabaergic and glutamatergic cell groups in the cuneiform nucleus, BP.PD

Abstract

The cuneiform nucleus (CUN) has traditionally been associated with locomotor activity, and many studies have considered the CUN to be part of the locomotion system. As a result, this structure has been viewed as a potential target for deep brain stimulation in Parkinson's disease (PD). However, recent studies have shown that the CUN has strong bidirectional connections with the dorsolateral periaqueductal gray (dlPAG) and shares a similar source of inputs that integrate information related to life-threatening events. For instance, optogenetic activation of CUN neurons generates innate freezing and antipredator flight responses in rats, with results from our lab showing that glutamatergic neurons drive defensive responses whereas GABAergic cells promote exploratory behaviors. In light of the dlPAG's role in mediating freezing or flight responses, this project aims to investigate the functional role of the connections between CUN and dlPAG in regulating defensive behaviors. To do this, we will use an in vivo single-cell electrophysiological approach combined with optogenetics to record the activity of dlPAG neurons while inactivating CUN inputs during exposure to a threat or a threat-associated context. Using phototagging, we will identify CUN neurons that project to the dlPAG and correlate their activity with different behavioral responses during the predator odor presentation. Using optogenetics with specific viral vector promoters, we will inhibit specific cell populations (e.g., excitatory/glutamatergic or inhibitory/GABAergic neurons) to characterize how distinct CUN cells modulate the firing rates of dlPAG neurons. Together, our proposed experiments will broaden our understanding of how the CUN functions beyond its traditionally described role in locomotion, specifically focusing on its contribution to anti-predatory defense mechanisms.