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Mental disorders account for 30% of the global disease burden. Anxiety disorders represent the highest proportion with conditions such as post-traumatic stress disorder (PTSD). Women are twice as likely to develop PTSD compared to men. Importantly, only a susceptible subpopulation of stressed individuals develops PTSD. Despite the identification of affected brain regions (e.g. hypothalamus, amygdala, periaqueductal gray), critical neuronal types, and their disbalanced circuit connectivity resulting in maladaptation are poorly understood.The sense of smell can contribute to induce PTSD. War Veterans with PTSD were distressed by the smell of burning rubber. We use all-optical voltage imaging ex vivo and in vivo and spatial transcriptomics to investigate maladapted and resilient neuronal connectomes of hypothalamic and periaqueductal circuits in olfactory predator stress model of PTSD. We aim to identify critical circuit motifs that underlie the susceptibility to develop PTSD-like state both in female and male mice to uncover sex-specific sensitivity resulting in the prevalence of PTSD in women.In summary, this research will explore genetically- and anatomically defined maladapted neuronal circuits ex vivo and in vivo to identify critical circuit motifs that predict susceptibility and development of long-lasting PTSD-like state. The intended research has high potential to reveal genetic therapeutic targets and strategies to reverse the circuit imbalance in PTSD.

Panic disorder (PD) has 2.5 times higher prevalence in women than in men. To develop effective treatment strategies for PD, it is crucial to examine the pathophysiology of brain circuits that are underlying the development of PD. Our research aims to investigate differences of circuit changes in female and male mice in panic-like states, which is of great translational value since the neurobiology underlying sex-difference in PD remains poorly understood at the circuit level.The periaqueductal gray matter (PAG) is critical for processing panicogenic stimuli. The anterior hypothalamic nucleus (AHN) responds to threats such as the proximity of predators. The ventromedial hypothalamus (VMH) induces defensive and panic-like behaviors in rodents and panic seizures in human patients. The VMH provides monosynaptic excitatory input both to PAG and to the AHN. The organization of defense reactions in the PAG utilizes inhibitory transmission, and the AHN consists of inhibitory neurons in 90%. However, the identity of the VMH-driven PAG and AHN neurons and the circuit motifs that process panic-related information from is poorly understood.In this research I propose to determine the key role of distinct inhibitory populations and circuit motifs of the VMH-PAG and VMH-AHN pathways in the development of panic-like state in male and female mice. The intended research has a high potential to reveal new genetic therapeutic targets and strategies to reverse the circuit imbalance in female PD.