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Estrogen: A Source of Femininity… and Stress Sensitivity?

Reference: Calvigioni, D., Fuzik, J., Le Merre, P., Slashcheva, M., Jung, F., Ortiz, C., … & Meletis, K. (2023). Esr1+ hypothalamic-habenula neurons shape aversive states. Nature Neuroscience, 245–1255.

Although you are probably aware of the biological differences between males and females, you may not be aware of the numerous differences when it comes to the brain. Until the 1980s, it was widely accepted that men and women were mostly the same biologically, with any differences in behavior attributed to social factors. Neuroscience research was primarily conducted in male participants due to this generalization. More recent research conducted on both male and female brains has found major differences in their brain’s structure and function ultimately impacting behavior.

Stress is an environmental factor that can alter the brain in many ways. Women are more likely to suffer from stress-related brain disorders including depression, anxiety, and post-traumatic stress disorder (PTSD) (1, 2). Although the exact cause of these prevalence differences remains elusive, neuroscientists have begun to unveil sex differences in brain pathways for behaviors influenced by stress. In a recent study conducted by researcher Daniela Calvigioni and colleagues, a direct link between aversive behavior and a stress-sensitive sex-hormone-dependent brain pathway was uncovered. These findings help paint a better picture of how female brains respond differently to stress and can inform specialized patient care for psychiatric disorders.

What Does Emotional Behavior Look Like in the Brain?

Emotions are often an internal drive for external interactions with the world. Emotions can also reflect our internal responses to what we are exposed to. For example, if a person is terrified of spiders and sees a spider near them, their emotionally driven response might be to run away or let out a scream. This scenario is an example of aversive behavior which is driven primarily by internal values intertwining with past external experiences, causing the individual to perceive the situation as negative and therefore avert themselves. The key brain regions linked to emotional behaviors are the prefrontal cortex and the lateral habenula. Neuroscientists often describe the brain as a hierarchal structure, with the top layer (i.e., the cortex) involved in the most complex behaviors, and the bottom part of our brain where our spine connects (i.e., the brainstem) more involved in automatic responses to the environment. Our cortex is seen as our rational decision-maker, using our emotional responses from stimuli processed by the brainstem to execute appropriate actions. But our cortex cannot do it all — intermediate brain regions act as a filter, integrating our values to determine the most important emotional signals to send to our cortex. The lateral habenula acts as a filter for our lateral hypothalamic area, which oversees sleep, feeding, and stress regulation among other key biological responses that require balance for survival.

Calvigioni’s study looked at how aversive behavior is coordinated through the lateral hypothalamic area, signaling to the lateral habenula to alter cortex functioning. In other words, the researchers wanted to better understand how information from our stress regulation station is filtered by our intermediate relay center, with the most important information sent to our decision maker to ultimately guide aversive behavior (see figure below).

Schematic of the lateral hypothalamic area (stress regulation center) sending information to the lateral habenula (relay station) to be filtered with the most important information sent to the prefrontal cortex (decision maker).

Estrogen’s Role in the Brain Affecting Emotional Aversive Behavior

The first part of this study looked at the types of neurons, or message carriers, within the stress regulation center that sends messages to the relay station. Using male and female mice, they found six major types of messengers based on various properties, with the most pertinent property for aversive behavior being the presence of binding sites for estrogen – the primary female sex hormone. Because females have more estrogen than men, estrogen-binding messengers in female brains have more estrogen available for their activation. I will refer to this specific subset of messengers as estrogen-positive stress signalers.

In the second part of the study, the researchers looked at how stimulating estrogen-positive stress signalers affected aversive behavior. The researchers inserted a light-sensitive binding site into the estrogen-positive stress signalers through genetic modification. Light can be surgically inserted into the stress regulation center and switched on and off by researchers to manipulate the stimulation of estrogen-positive stress signalers to the relay station. Activating these messengers for a short period of time resulted in aversive behavior immediately after, and prolonged stimulation of these messengers led to persisting aversive responses. They tested aversive responses through a “looming stimulus” test, where animals were placed in a box with a growing black hole presented at the ceiling. This reliably causes animals to either attempt to escape or freeze in place. The chosen behavior was recorded along with how long it took to escape or how long the animals froze in place (aversive responses). They also found our decision maker’s overall activity was altered by activating estrogen-positive stress signalers to the relay station. This outcome suggests that the aversive behavior is a result of the bottom-up flow of information from our stress center influencing our actions that are female sex hormone specific.

After establishing a female sex hormone-specific pathway in the brain for aversive behavior, the researchers next wanted to determine the sex-specific effects of stress on this pathway impacting behavior. The scientists used unpredictable foot shock stressors before behaviorally testing animals. Females showed increased aversive responses to stress in comparison to males, and silencing estrogen-positive stress signalers genetically prevented the aversive response only in females.

When singly looking at estrogen-positive stress signalers, their internal properties looked different to females who had not experienced stress. There were no differences seen between normal and stressed males, suggesting these messengers were increasingly sensitive to stress in females. These findings uncovered a new brain pathway influenced by sex hormones and important for aversive behaviors impacted in stress-related disorders. This specific group of stress regulation messengers could be a mechanism underlying sex differences in stress-related disorders. Targeting estrogen-positive stress messengers could become a novel treatment in females with stress-related disorders impacting aversion and fear responses relevant to disorders like anxiety and depression.

Conclusions

Neuroscience research has the lowest inclusion of females when compared to any other biological system. It is crucial that female systems are used in medically translatable research to ensure everyone receives the most effective and personalized care. Hopefully, this study inspires further research into neuro-stress regulation differences in males and females, relevant to many developmental and age-related disorders of the brain from attention deficit hyperactivity disorder and anxiety to Alzheimer’s disease that have sex differences in their prevalence ratios. Animal and human studies have shown that brain regions involved in stress and memory have sex differences that can be both structural and functional (2-6). Further research investigating these brain regions and their role in psychiatric illness will improve the treatment and therefore quality of life for underrepresented patients with female brains, especially in disorders involving stress and memory.

Additional References:

  1. Swaab DF, Bao AM. Sex differences in stress-related disorders: Major depressive disorder, bipolar disorder, and posttraumatic stress disorder. Handb Clin Neurol. 2020;175:335-358. doi: 10.1016/B978-0-444-64123-6.00023-0. PMID: 33008536.
  2. Bangasser DA, Wiersielis KR, Khantsis S. Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress. Brain Res. 2016 Jun 15;1641(Pt B):177-88. doi: 10.1016/j.brainres.2015.11.021. Epub 2015 Nov 21. PMID: 26607253; PMCID: PMC4875880.
  3. van Eijk L, Hansell NK, Strike LT, Couvy-Duchesne B, de Zubicaray GI, Thompson PM, McMahon KL, Zietsch BP, Wright MJ. Region-specific sex differences in the hippocampus. Neuroimage. 2020 Jul 15;215:116781. doi: 10.1016/j.neuroimage.2020.116781. Epub 2020 Apr 9. PMID: 32278894.
  4. Spets DS, Slotnick SD. Are there sex differences in brain activity during long-term memory? A systematic review and fMRI activation likelihood estimation meta-analysis. Cogn Neurosci. 2021 Jul-Oct;12(3-4):163-173. doi: 10.1080/17588928.2020.1806810. Epub 2020 Aug 19. PMID: 32812492.
  5. Goldstein JM, Lancaster K, Longenecker JM, Abbs B, Holsen LM, Cherkerzian S, Whitfield-Gabrieli S, Makris N, Tsuang MT, Buka SL, Seidman LJ, Klibanski A. Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses. Psychiatry Res. 2015 Jun 30;232(3):226-36. doi: 10.1016/j.pscychresns.2015.03.006. Epub 2015 Mar 31. PMID: 25914141; PMCID: PMC4439265.
  6. Gall CM, Le AA, Lynch G. Sex differences in synaptic plasticity underlying learning. J Neurosci Res. 2023 May;101(5):764-782. doi: 10.1002/jnr.24844. Epub 2021 Apr 12. PMID: 33847004; PMCID: PMC10337639.