Women are twice as likely as men to experience an affective disorder, such as depression, anxiety, and post-traumatic stress disorder (PTSD). This clinical reality suggests that biological sex confers susceptibility and resilience to these devastating mental illnesses, yet biological mechanisms conferring this sex bias in vulnerability remain unknown. Research in the Lucas Lab is committed to discovering the specific mechanisms driving sex differences in brain and behavior.
Sex-Specific Brain Circuits for Emotional Memory
The emotion of fear is a powerful trigger for memory storage, helping us avoid cues associated with dangerous outcomes. However, fear memories become maladaptive in common psychiatric diseases disproportionately experienced by women, such as post-traumatic stress disorder, generalized anxiety disorder, panic disorder, and phobia. By understanding how females encode and express fear memories differently than males, we will be able to pinpoint sex-specific mechanisms and treatment strategies for fear-based psychiatric disease. We use a variety of techniques to pinpoint specific brain circuits and neuron subtypes underlying fear memory dynamics, including whole-brain mapping, activity-dependent neuronal tagging, and electrophysiology. We then establish causal relationships between these observations and maladaptive emotional responses by activating and silencing these pathways with chemogenetic or optogenetic tools. Our long-term goal is to discover novel brain circuits driving conditioned fear behavior in females.
Tiled Light Sheet Microscopy Image
Naive - Heat Map
Fear Memory - Heat Map
To uncover sex differences in neural network activity after a behavioral experience, we clear brains with iDISCO+ and quantify the number of neurons expressing the neural activity marker c-fos with ClearMap. This light sheet microscopy image (left) depicts a snapshot of neural activity (c-fos expression) evoked by fear memory recall. Image courtesy rotation student Haley Edwards. Heat maps generated in collaboration with Dan Bloodgood of Dr. Thomas Kash’s lab at UNC Chapel Hill.
Influence of Gonadal Hormones on Brain Function and Behavior
Epidemiological data show that women are most susceptible to affective spectrum disorders during reproductive viability: before puberty or after menopause, the prevalence of these disorders between the sexes is equivalent. This clinical reality suggests that puberty onset and circulating sex hormones confer women’s susceptibility to such disorders. Our lab investigates how gonadal hormones orchestrate brain function and behavior by focusing on puberty onset in adolescent mice and the estrous cycle in adult mice. We are particularly interested in (1) how stress during puberty may permanently re-wire the brain the promote susceptibility to affective disorders and (2) the anxiolytic actions of endogenous estrogen in naturally cycling females. We use a combination of genetic, electrophysiological, and pharmacological tools to tackle these questions.
Left image, amygdala interneuron courtesy of undergraduate lab member Averie Bunce.