Humans have developmentally programmed sex differences throughout our entire brains. Our neurons connect and act like a switchboard to form a neural circuit system and our entire brain is filled with and propelled by sex hormones (via both nuclear and nonnuclear receptors.) These hormones can affect cognitive function, mood, neuroprotection, addiction, blood pressure, fine motor skills, motor coordination, and pain.
In 1979 research found that sex hormones facilitate sex behavior via receptors in the hypothalamus. We know that the main location of receptors is in the hypothalamic region and amygdala, but their behaviors and neurological states are also influenced by estrogens involving brain regions. Not every hormone action happens through cell nuclear receptors, some happen through receptors from a variety of signaling pathways; such as steroid hormones like vitamin D, aldosterone, antiandrogens, estrogens, and progestins. When changes occur, sex hormones can alter brain structure as well as functional plasticity. There are also so-called latent sex differences, meaning those that appear only under certain conditions such as following injury, exposure to environmental toxins or to physical and psychological stressors. All brains are similar at baseline but have different neurochemical underpinnings that can result in different vulnerabilities or divergent outcomes in response to the same stressor.
Some of the developmental sex differences come from the release of sex hormones during periods in development, but they are also contributions of our genes when it comes it our X and Y chromosomes. In females, these hormones create the inactivation of one or the other X chromosome.
Our mitochondrial genes make important contributions to the brain and bodily functions, and we’ve found that there are some fundamental differences between males and females in this regard.
The differences are very subtle and are associated with patterns of connectivity (back to our circuit board) and areas of our brains. Studies have only been done on animals for pretty obvious reasons, but they found sex differences in not only neurochemicals and mechanisms, but also in physical brains which lead scientists to believe that there might be similarities between human brains, as well.
One receptor we see in females (rats, in this case), is when the NMDA receptor, when activated, works with activation of estradiol to stimulate signaling pathways within cells. A signal in the pathway leads to a thing called “cofilin phosphorylation.” When this happens, this path activates your hypothalamus and takes part in creating “lordosis behavior.” Lordosis behavior is the body posture and behavior that is typically seen as a way for female copulation, AKA the position that allows you to be mounted.
Estrogen has other functions aside from sexual activity such as protecting neurons from damage when things like seizures or strokes happen and the effects of Alzheimer’s disease. Our brain is actually capable of creating estrogen, either from androgens and potentially from cholesterol. Essentially, estradiol, when needed, can act a protector. We can also locally generate androgens outside of the gonads (the ovaries or testes) which can help protect us in different ways.
These sex differences happen throughout your life through genetics and epigenetics. The difference? Genetics are the things passed down from our parents which stay the same throughout our lives and will be passed on to the next generation. Epigenetics is the turning off and on of what our genes say (think light switch). There are factors that can affect our genes, allowing them to do things or not that would not be passed down to your children or change the underlying structure of your DNA; usually caused by environment or other factors; stress, for instance.
Things like stress can have effects on the hippocampus and prefrontal cortex, the dopaminergic system, blood pressure control, the cerebellum, and pain sensitivity. Stress can affect male and female rats in different ways. A study placed rats under chronic stress for 21 days and found that the male rats dendrites (the root looking signal carriers) had reactions and lost a significant amount of PARV (a calcium-binding albumin protein) neurons that play a role in physiological processes and are signaling proteins that can release neurotransmitters and regulate the communication in each cell. But in female rats, this didn’t happen. Not only did it not hinder female rats, it did the opposite. Chronic stress on hippocampus-dependent memory impaired male rats and either had no effect on females or actually enhanced their memory. The exposure also had opposite effects on classical eyeblink conditioning which is used by scientists to test neural structures and mechanisms that underlie learning and memory. It was inhibited in females and enhanced in males, leading us to believe that the effect was inhibited due having ovaries (making it estrogen dependent).
Even more, there seems to be a developmental component to the effects of stress on the sexes. There are different effects of chronic stress on dendrite length and branching, rats pre-puberty have similar responses to stress, but after sexual maturation there are differences.
Stress is handled in many different ways, but one major concern we are having as a society is opioid abuse. When estrogen is higher, compared to low estrogen in males, there are receptors that are actually physically positioned differently to enhance excitability and changed the way they were able to comprehend and learn to make it a pathway and process; these changes affected their levels of excitability and primed them for wanting for opioids. Because women are more sensitive to stress and actually can have better cognitive performance following stress this actually may have an effect on being more addiction prone, especially in terms of opioids- because of these sex differences in female and male opioid receptors. When you get excited easily and like it, your brain remembers this feeling and wants to do it again- addiction.
So, chronic stress has the opposite effect on the hippocampal opioid system in males and females. Studies show that with 10 days of chronic stress, males shut off their opioid system but in females (regardless of levels of estrogen) it gets to a state that is ready for greater excitement- priming. When researchers then gave the females oxycodone (a popular opioid, that is chronically abused) they had different effects when it kicked in if they were stressed or not and in the hour following when it wore off, it changed their learning processes based on their level of stress making them more excited and primed for more opioids.
Effects of estrogen are widespread in the CNS and can have implications on pain circulation. We also see a difference in the ability of estrogen to promote dopamine release. In the prefrontal cortex, local estradiol application mimics the effects of high estrogen in your entire body which promotes memory rather than a response memory bias, interacting with the dopamine throughout your body. Dopamine is the neurotransmitter that helps control the brain’s reward and pleasure centers which are associated with exciting behaviors like sex and gambling. Estradiol regulates dopamine release from striatum in a sexually dimorphic manner in the hippocampus and elsewhere in the brain. The hippocampus is primarily responsible for the processing of long-term memory and emotional responses. See the connections between hormones, happiness, excitability, emotions, and memory?
The cerebellum which is responsible for balance and coordination of muscles and the body also reacts to estrogens and creates estradiol and progesterone during development. We see that this can have implications in humans on disorders that actually show our sex differences. These estrogens work with the growth of the dendrites that regulate the balance of our excitable and inhibitory balance. Meaning this can actually affect not only the primary responsibility of the cerebellum of motor coordination but also our memory and mood regulation. We see these negative effects in disorders like ADHD and schizophrenia in males. With the connections to our muscles and bodies, estrogen can have an influence on how we learn to manage pain and can cause differences in sex pain management. A study found that chronic pain conditions in women could actually be connected to these differences in development in the cerebellum. With regards to pain management, clinical trials have shown that morphine is less effective on women than men and this could be related to sensory processing based on levels of testosterone.
Pain in regards to migraines is more prevalent in women and might be connected to a sex phenotype. Their findings quoted from the study say that “sex differences involve both brain structure as well as functional circuits, in that emotional circuitry compared with sensory processing appear involved to a greater degree in females than males.”
Through studies with humans, rats, and other animals we are shown that there are differences in mood, cognitive function, blood pressure regulation, motor coordination, pain, and opioid sensitivity when it comes to our sex and brain differences. We know that the differences are subtle and usually connected to these sex hormones, genetics, and epigenetics. Research seems to indicate that there are differences, but the implications that these differences make on everyday life isn’t certain nor are all of the factors that go into these implications. As well, these differences are chemical interactions and not one person is the same. These chemicals that traditionally make up our body types are different and with more or less of a certain one, different outcomes will happen. One brain isn’t better or stronger or more capable of doing a certain thing, it might have a different predisposition to do something based on genes or even external factors- such as conditioning to think they are more capable.
With neuroscience still being a relatively young practice, I’m sure we’ll see many more studies to come which can hopefully explain more. For now, take all of these findings with a grain of salt and remember that no matter, if you are a male, female, or non-gender conforming, don’t let any societal implications of gender hinder you from doing things you want to do!
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McEwen, B. S. and Milner, T. A. (2017), Understanding the broad influence of sex hormones and sex differences in the brain. Journal of Neuroscience Research, 95: 24–39. doi:10.1002/jnr.23809