Sex and Gender: Are they in your pants? In your genes? Or in your brain?

Humans love putting labels on things. Especially other humans. One of the biggest debates across history is what defines the sexes. What is a woman? What is a man? What about those who aren’t quite either? And are they all really that different? As we have learned more about hormones, brain development, and genes, the conversation has only become more complicated.

Many social scientists have proposed the idea that gender is mostly, if not entirely, socially constructed. The neuropsychologist Gina Rippon (1) appears to neglect decades of scientific data to support such a view. In her recent book, “Gender and Our Brains: How New Neuroscience Explodes the Myths of the Male and Female Minds”, she suggests that much of scientific data on gender differences is misguided because girls and boys are treated differently since birth, and so environment is what causes apparent gender differences in brain and behavior. Brains are highly plastic (able to change), especially in early development, which Rippon asserts is the reason that they can so easily be molded to fit a society’s expectations for gender. She cites an example in which children view a video of someone being hurt while receiving an fMRI, which allows researchers to see which parts of the brain are active, and by how much. The children were asked how badly they felt watching the videos, as a measure of empathy. The girls tended to report more empathy as they aged, and the boys, less. However, their brain scans revealed the same amount of activity in the areas associated with empathy, regardless of age or sex. This implies that the children are filtering what they say they feel in order to conform to ideals of feminine and masculine behavior.

The flaw in Rippon’s argument is that she has blurred the distinction between gender roles, and aspects of gender identity and sexually differentiated brain physiology that are not expressed as behavior at all. By pushing the idea that biologist see sex as binary rather than along a continuum, she creates a false narrative that scientists are only looking for discrete differences between sexes, instead of trends.  However, there is a wealth of data showing that our physiology, including our brain and sensory functions, are influenced by genes and hormones to create a continuum of responses in individuals that identify as male and female that are beyond the reach of cultural norms. All of these processes contribute to the expression of gendered behavior, which is culturally constructed, and gender identity, which has both biological and societal influences.  Gender identity is how one perceives oneself and feels appropriately identified by the cultural labels of woman, man, or other. It may or may not translate into acting feminine, masculine, or androgynously.

To provide just one example that gender identity has a biological brain component, researchers (2) examined all the coding DNA sequences, the DNA that codes for proteins, in a sample of 30 transgender individuals. Genes associated with hormone pathways that determine whether a brain is likely to be typically feminine or masculine were different in these individuals, but not in the general population. This means differences in hormone function during development may be why some people feel like women, some like men, and some like something else.

The mysteries of human nature may never be fully explained, but accepting the idea that biology and culture both contribute to who we are can keep bringing us a little closer.

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1. Do men and Women have different brains? The New York Times (https://www.nytimes.com/2019/09/09/books/review/gender-and-our-brains-gina-rippon.html). Original book: Rippon, G. (2020). Gender and our brains: How new neuroscience explodes the myths of the male and female minds. Vintage.
2. Medical College of Georgia at Augusta University. (2020, February 5). Gene variants provide insight into brain, body incongruence in transgender. ScienceDaily (www.sciencedaily.com/releases/2020/02/200205084203.htm). Original article: J. Graham Theisen, Viji Sundaram, Mary S. Filchak, Lynn P. Chorich, Megan E. Sullivan, James Knight, Hyung-Goo Kim & Lawrence C. Layman (2019) Gene variants provide insight into brain, body incongruence in transgender. Scientific Reports 9, 20009

Laura West

Department of Biology

University of Mississippi

Effects of Dietary Enrichment on Behavior and Neurogenesis

Lack of protein can harm outward appearance, stress sensitivity, and learning by impairing brain growth and plasticity. While protein enrichment is well studied in mammals and poultry birds, little is known about protein impacts for most birds. Thus, we are studying protein enrichment in the zebra finch, a common avian lab model because its song learning mimics human language learning. While zebra finches mainly eat seeds, protein is increased by consuming insects and young seeds, especially during breeding, and may be beneficial in captivity.

A poor diet results in an unhealthy appearance in humans? Normally, female zebra finches are attracted to males with big, bright, red cheek patches. Since low protein may reduce attractiveness, we will quantify the size and color of male cheek patches and test mate preferences of birds on low and high protein diets. We expect males and females will prefer to associate with mates fed high protein diets.

Ever go on a fad diet and find yourself irritated and jumpy? If a healthy diet lowers stress in zebra finches, baseline and reactive stress hormone levels, the latter induced by holding birds in a breathable cloth bag for 30 minutes, will be lower when fed high protein.

The Escape Maze	Fear Conditioning Chamber

We will test two forms of learning: spatial learning and classical conditioning to determine if, like mammals, protein aids learning. The Escape Maze tests birds’ spatial learning, the ability to store and recall locations. We test spatial ability by seeing how many trials it takes for birds to learn to escape a clear cylinder using visual cues hanging around the maze to triangulate the escape hole’s position. In Fear Conditioning, birds are placed in a box, a tone plays, and a small shock is delivered. Birds should learn to take flight to avoid the shock when they hear the tone, similar to Pavlov’s dogs salivating when a bell rang. We expect that a high protein diet will help birds learn at a faster rate than a low protein diet.

After behavioral tests, we will determine if high protein aided brain growth and plasticity in the areas of the brain involved in anxiety, spatial ability, and fear conditioning. If protein has positive impacts, we suggest all lab zebra finches be providing protein supplementation. Such results would suggest that despite inconsistent protein in the wild, zebra finches, like mammals, have an evolutionarily conserved benefit from protein, the building block of life.

Citations:

1. Bonaparte, K. M., Riffle-Yokoi, C., & Burley, N. T. (2011). Getting a Head Start: Diet, Sub-Adult Growth, and Associative Learning in a Seed-Eating Passerine. PLoS ONE, 6(9). https://doi.org/10.1371/journal.pone.0023775
2. Burley, N. T., Hamedani, E., & Symanski, C. (2018). Mate choice decision rules: Trait synergisms and preference shifts. Ecology and Evolution, 8(5), 2380–2394. https://doi.org/10.1002/ece3.3831
3. Paula-Barbosa, M. M., Andrade, J. P., Castedo, J. L., Azevedo, F. P., Camões, I., Volk, B., & Tavares, M. A. (1989). Cell Loss in the Cerebellum and Hippocampal Formation of Adult Rats after Long-Term Low-Protein Diet. Experimental Neurology, 103, 186–193.

Belinda Bagwandeen

PhD Student, Day Lab

Biology

NEUROSTEROIDOGENESIS AS THERAPEUTIC STRATEGY TO COMBAT HORMONAL DYSREGULATION IN HIV-1 PATIENTS

by Salahuddin Mohammed

Graduate Research Assistant, Paris Lab

School of Pharmacy, Division of Pharmacology

Schematic diagram of hypothalamus, pituitary, adrenal gland axis, the problems resulting from dysregulation of this axis leading to increased corticosterone , and the hypothetical use of TSPO (a protein that transports the substrate for making hormones, cholesterol, to the mitochondria) to initiate steroidogenesis thereby correcting the imbalance in corticosterone to reduce anxiety, depression, and other psychiatric complications.

Would you like to humor your stress levels? We bet you would!

Experiencing weight gain and chronic health issues-blame it on cortisol, the hormone produced by adrenal glands and the HPA (hypothalamus, pituitary gland & adrenal gland) axis controls its secretion.

Cortisol gained popularity as the essential hormone that triggers our fight-or-flight response or as the “death hormone.”

Now there is more to this hormone.

Cortisol is not always bad for our body. It is responsible for many essential functions. It acts as our internal timekeeping clock, also known as circadian rhythm. This circadian clock assists us with getting up toward the beginning of the day by increasing cortisol and diminishes as the night advances by permitting melatonin levels to increase in the body, which permits us to sleep.

Most importantly, it prepares our body for the “fight or flight” response by mobilizing the energy stores to fight the stressor. However, once the stressor is subsided, cortisol levels should decline, and our body goes back to normal. However, what happens when we are in a constant condition of stress? A few issues related with constant undeniable degrees of stress are anxiety, depression, lack of concentration, focus, attention and memory and energy, digestion and sleep problems, headaches and heart complications.

Nonetheless, these issues are connected to undeniable degrees of stress and not reliably significant degrees of cortisol. Low cortisol levels are related with a few medical problems, like Addison’s disease, which can cause: Fatigue, loss of hunger and weight, nausea, vomiting, muscle weakness and skin color changes.

The HPA axis (hypothalamus, pituitary, and adrenal glands) regulates cortisol levels. This body axis needs to work synchronously for our hormones to be at optimal levels.

How is this related to HIV?

The current antiretroviral drug regimen has come as relief for HIV infected patients as they live longer but these patients demonstrate neurological and neuroendocrine (HPA axis) dysfunction and we hypothesize that HPA axis dysfunction may contribute to the neurological deficits. HPA axis dysfunction is common in HIV infected patients wherein they demonstrate increased basal cortisol levels compared to normal population, oddly, despite increased cortisol their adrenal glands respond insufficiently when exposed to a stressor. Our lab is working to understand the underlying mechanisms for HPA dysfunction in a transgenic mouse model that has a specific gene, Tat, known to be at high levels in the brains of HIV-1 patients.  We are using this model to determine how to reduce excess cortisol which may increase vulnerability to other neuropsychiatric complications. Neurosteroids (steroids formed in brain) have shown to confer neuroprotection and modulate the hypothalamic-pituitary-adrenal (HPA) axis. Thus, we are exploring the capacity to boost neurosteroidogenesis via TSPO activation (rate limiting step for neurosteroidogenesis) or Allopregnanolone (potent allosteric GABA_A receptor modulator) administration, as a therapeutic strategy to reduce HPA dysregulation and comorbid affective and stress-sensitive neuropsychiatric disorders.

1. Salahuddin MF, Mahdi F, Sulochana SP, Paris JJ. HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone Psychomotor Effects in Female Mice. Viruses. 2021 Apr 30;13(5):813. doi:10.3390/v13050813. PMID: 33946474; PMCID: PMC8147167.
2. Salahuddin MF, Mahdi F, Paris JJ. HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice. Int J Mol Sci. 2020;21(21):8212.
3. Salahuddin MF, Qrareya AN, Mahdi F, Jackson D, Foster M, Vujanovic T, Box JG, Paris JJ. HIV-1 Tat protein and oxycodone dysregulate adrenal and gonadal endocrine axes and promote affective and cognitive dysfunction in Mice. Hormones and Behavior, 2020; 119:104649.
4. Paris JJ, Liere P,  Kim S , Mahdi F , Buchanan ME , Qrareya AN,  Mohammed SF , Pianos A , Fernandez N , Shariat-Madar Z, Knapp PE , Schumacher M, Hauser KF. Physiological Allopregnanolone is Neuroprotective against Combined HIV-1 Tat and Morphine-Induced Neurotoxic and Psychomotor Effects. Neurobiology of Stress. 2020; 12: 100211.

For the Birds: Can Toys Reduce Stress and Improve Science?

Laura West

Masters Candidate, Biology

Enrichment is a common way to reduce stress in captive animals. Examples of enrichment include novel food supplements, or opportunities to exercise and play. Such environmental stimulation is an important part of keeping animals mentally and physically healthy. If animals are bored, they can become stressed and sickly, which hurts the animals, and can reduce the accuracy of results that are meant to be studies of normal rather than stressed animals¹. Because the way zebra finches learn to sing is similar to how humans learn language, they are popular animals to study in labs. Living in a lab can be stressful even when given basic necessities such as food and water. Stress, in turn, can harm birds’ learning abilities², encourage repetitive behaviors¹ and make them more afraid of new places and things³. Enrichment may counteract these effects, but it has not been well-studied in zebra finches.

In my research, I will see if providing finches toys and natural perches can lower stress levels over time, improve learning, reduce boredom, and decrease anxiety and fear of new things. These toys include a silver bell, linked plastic rings and a small wooden ball. I will compare stress hormone levels in birds given enrichment to those in standard cages. I will video record the birds daily, and quantify repetitive behaviors such as pulling out their own or others’ feathers, which are signs of boredom. To see if having toys makes the birds less afraid of new things, I will do a test in which I put novel object in the birds’ cages, and record how long it takes for birds to investigate the new object. Anxiety is measured by comparing how long birds spend in the open center portion of an unfamiliar box to the amount of time they spend clinging to the walls. Finally, we will test the birds ability to remember a rewarding location by having them escape from a clear cylindrical maze. This task is particularly important, because this part of the brain used to record these types of spatial memories, the hippocampus, is especially harmed by stress.

This research is important for the the welfare of the birds and for the validity of scientific research. Happy birds make happy researchers.

Morality before Religion

 

 

 

Chromosome Caps Can Predict Cognitive Decline during Aging

It is no secret that everyone ages. Humans do not stay frozen at a specific age. They age, and when they age there are declines in processes such as metabolism and cognition. A recent study investigated why there may be a loss of cognition with age. One answer is the length of the telomere!

Telomeres are DNA-protein complexes capping the chromosomal ends (see Figure). Telomeres shorten each time the cell divides and when they become too short, the cell will become damaged and die. The accumulation of cell damage due to telomere shortening is thought to be a major cause of the symptoms of aging. In the current study (1), telomere length was measured in 497 individuals. The individuals had their blood taken when they were young adults. They also completed tests to assess their cognitive function. Then 13 years later, these same individuals had their blood taken and were tested again. Using the blood samples, the experimenters extracted DNA from their white blood cells and measured the telomeres on their chromosomes. During the study, multiple factors were considered to account for variability between subjects, such as sex, ancestry and socioeconomic status. The study found that there was a connection between telomere length and global cognition that withstood all demographic factors measured by the study. Specifically, the greater the rate of shortening of the telomere, the worse the cognition. Aspects of cognition such as information processing speed, memory, and visual-spatial awareness all declined in relation to the shortening of the telomere. Previous studies made connections between the loss of cognition and age, but no studies have made the connection between shortening of the telomere and loss of cognition.

This study opens up the door to an efficient and simple method that could lead to early detection of cognitive decline in older adults. Everyone ages; there is no denying that fact of life, but this study has the potential to reduce the amount people suffer with age.

1. Cohen-Manheim, I., Cohen-Manheim, I., Doniger, G. M., Doniger, G. M., Sinnreich, R., Sinnreich, R., . . . Kark, J. D. (2016). Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife. European Journal of Epidemiology, 31(2), 147-157.

Cat Kania

Department of Biology

University of Mississippi

Sex Hormones Can Protect Neurons from Ischemia

Research on potential treatments for stroke and other brain injuries has recently focused on the brain’s ability to protect, heal, and repair itself after injury. Estradiol, a sex hormone, is a well-established mediator of the brain’s healing process. However, the processes by which estradiol initiates protection and repair after an injury are still under research. Recent research into a protein in the brain known as Cocaine- and Amphetamine-Regulated Transcript (CART) has shown this neuropeptide to play a role in the neuroprotective actions of estradiol. Previously, scientists believed CART was an important messenger that impacted appetite suppression, drug satisfaction, stress, and cardiovascular function. However, in a recent study, CART was found to enhance recuperation of the cerebral cortex after an ischemic stroke (1).

Ischemia is a condition characterized by insufficient blood flow, which causes a shortage of oxygen that is necessary for cellular metabolism; therefore, ischemia leads to dysfunction and death of cells including neurons. CART expression after ischemia reduced neuronal cell death and DNA damage by 37-59% (see Figure). CART-related neuroprotection was greatly increased by the presence of estradiol. Further, CART inhibition reduced the neuroprotective effects of estradiol. Therefore, CART is believed to be an important component in estradiol-mediated neuroprotection.

These results demonstrate that CART is protective against neural injury on its own and that expression of CART is greatly increased by estradiol. Therefore, stroke patients with reduced estradiol levels may experience a reduction in not only neuroprotective processes directly triggered by estradiol but downstream targets of estradiol as well. Thus, these findings impact our understanding of Hormone Replacement Therapy in stroke-injured brains as well as promote the investigation and development of therapeutic agents for treatments based on homology to CART.

1. Xu, Y., Zhang, W., Klaus, J., Young, J., Koerner, I., Sheldahl, L. C., . . . Alkayed, N. J. (2006). Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection. Proceedings of the National Academy of Sciences of the United States of America, 103(39), 14489-14494.

Logan Boutwell

Department of Biology

University of Mississippi

HIV-1 Tat Protein and Oxycodone Dysregulate Hypothalamic Pituitary Adrenal axis and Promote Affective and Cognitive Dysfunction in Mice

Human immunodeficiency virus (HIV) is associated with co-morbid affective and neurocognitive disorders that afflict ~50% of infected individuals. One factor that may contribute to neuropathology is the HIV regulatory protein, trans-activator of transcription (Tat), which promotes neuroinflammation and neurotoxicity that can be exacerbated by opioids. We and others have observed steroid hormones, such as estradiol and/or progesterone, to attenuate Tat-mediated neurotoxicity in cell culture; however, their interactions with opioids and their protective effects in a whole-animal model are unknown.

We hypothesized that doxycycline-inducible expression of Tat in transgenic mice would interact with the opioid, oxycodone, to induce psychomotor, anxiety-like, and depression-like behavior and to dysregulate hypothalamic pituitary adrenal (HPA) axis. When administered acutely, oxycodone (3 mg/kg) increased psychomotor behavior in an open field and induction of HIV-1 Tat protein significantly potentiated these effects. Tat expression also potentiated the anxiolytic-like effects of oxycodone, increasing entries into the center of the open field, but only among females in the diestrous phase of the estrous cycle. Tat increased depression-like behavior among proestrous, but not diestrous, females. When administered oxycodone (3 mg/kg, QD for 5d) repeatedly expression of Tat protein interacted with estrous cycle of mice to decrease cognitive performance in a novel object recognition test in proestrous mice.

These data suggest that induction of Tat potentiates psychomotor and anxiety-like effects of acute oxycodone and either Tat induction or repeated oxycodone perturb cognitive performance. Manipulations also influenced HPA axis. Tat or oxycodone increased circulating corticosterone in all mice acutely and repeated administration produced greater elevations. Tat-neurotoxicity in differentiated SH-SY5Y cell cultures is ameliorated by estradiol or progesterone and does not interact with oxycodone. Thus, neuroendocrine function may be an important target for HIV-1 Tat/opioid interactions.

Salahuddin Mohammed

Department of Biomolecular Sciences

University of Mississippi

Controllability: Does it change our perception?

Imagine a wild dog is running towards you and there is no escape. You are helpless and will have to face the consequence of the attacking dog. Now imagine that you are standing in an open doorway. Now you know that you have control of the situation and can prevent the dog from attacking you by closing the door. In this hypothetical example of the wild dog, how does your brain respond the moment it knows you have control over the outcome of the situation? Currently, few studies have compared the brain’s response to cues indicating aversive (or rewarding) events in uncontrollable and controllable circumstances.

The behavioral response to rewarding and aversive events in the human brain depends on the context of the situation. Controllability refers to the degree in which an individual can influence the situations outcome. Every day we experience scenarios in which we are rewarded for specific behaviors. Additionally, if we fail to behave appropriately we are faced with various forms of punishment. Sometimes, these rewards and punishments are perceived as controllable and sometimes they are not.

The goal of my research is to identify the brain’s response to cues preceding controllable and uncontrollable rewarding and aversive events. Electroencephalography (EEG) and event-related potentials (ERPs) will be used to identify the neuronal activity in response to these events. Participants will complete a task in which geometrical symbols are paired with controllable and uncontrollable aversive and rewarding events on the screen of a computer. Referring to the example of the wild dog, some of these symbols represent the presence of the door (choice vs. no-choice), while some of these symbols represent the intention of the dog (aversive vs. reward). Understanding how the brain processes controllability is important to better understand anxiety disorders in humans.

Tyler West

Health and Exercise Science

University of Mississippi

Learning through Reward or Punishment: Can Our Brains Perceive the Difference?

One of the primary ways we learn a new skill is through our teachers providing feedback in the form encouragement or criticism. This feedback is very valuable to learning and is meant to incentivize the learner to improve their upcoming performance. But are there some types of feedback that can hinder to skill learning? Recently, researchers have focused on how reward and punishment affect skill learning and retention. These studies demonstrate that punishment feedback enables faster learning but diminishes task preservation. Whereas reward feedback, promotes both learning and retention (1). Additionally, reward and punishment feedback activate different areas of the brain (2). Collectively, these studies suggest reward and punishment have distinguished effects behavior and our brains. However one question still remains: How are these types of feedback actually changing our brain during the process of learning and retention? Currently, no study has looked at how reward and punishment affect the moment to moment processes of the brain after receiving the feedback.

In our lab we sought to answer this question by utilizing electroencephalography to monitor feedback event related potentials (ERPs), a distinct change in the neural activity associated with feedback, in human participants after they received a monetary reward, monetary punishment, or no feedback as they attempted to learn and retain a novel visuomotor rotation task. During the learning stage, we found that all groups learned the task at the same rate and there were no differences in the feedback ERP amplitude (strength of the electrical signal) across all groups. However, during retention testing, the punishment group failed retain the task and their feedback ERP amplitude decreased. Whereas reward and null maintained a similar performance and ERP amplitude throughout retention testing.

But what does this mean? Feedback ERPs have been associated with how our brains represent the motor task (3). We suggest that punishment interferes with the brain processes that are responsible for how our brain stores motor tasks by taking away resources used for learning and retention, to avoid the aversive outcomes. Thus punishment may not be suitable for creating long-term changes in learner’s performance.

So, if we ever find ourselves providing guidance for a new learner, let’s keep in mind how we provide direction not only affects how your pupil learns, but also affects how their brain prepares for the task in future.

1. Galea, J. M., Mallia, E., Rothwell, J., & Diedrichsen, J. (2015). The dissociable effects of punishment and reward on motor learning. Nature Neuroscience, 18, 597-602.

2. Steel, A., Silson, E. H., Stagg, C. J., & Baker, C. I. (2019). Reward and punishment differentially recruit cerebellum and medial temporal lobe to facilitate skill memory retention. Neuroimage, 189, 95-105.

3. Palidis, D. J., Cashaback, J. G., & Gribble, P. L. (2019). Neural signatures of reward and sensory error feedback processing in motor learning. Journal of Neurophysiology, 121, 1561-1574.

Christopher Hill

Health and Exercise Science

University of Mississippi