by Salahuddin Mohammed
Graduate Research Assistant, Paris Lab
School of Pharmacy, Division of Pharmacology
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 GABAA receptor modulator) administration, as a therapeutic strategy to reduce HPA dysregulation and comorbid affective and stress-sensitive neuropsychiatric disorders.
- 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.
- 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.
- 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.
- 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.
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!
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.
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.
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.
Though we come to realize more and more how similar we are to one another, there remain certain slight differences between sexes across the animal kingdom. In humans and other mammals like mice and monkeys, many studies have revealed a sex difference in spatial memory. Spatial memory is how you know where things are in relation to yourself and other things, whether they be objects, places, or other people, and the ability to use this information to navigate yourself wherever you want to go. It appears that while overall spatial memory performance is similar between sexes, males have an initial upper hand due to the use of more efficient strategies to acquire a new spatial memory. The reason for this difference seems to be the simple fact that male mammals use their spatial memory more than females, most often for seeking out females across their territory. This reflects a property of the brain that many refer to as “use it or lose it” but that might be more accurately put as “don’t need it, don’t develop it,” though not quite as catchy. In birds, this feature of spatial memory can be seen even more clearly. For example, brown-headed cowbirds are brood parasites such that the female seeks out suitable host nests in which to lay her eggs and then remembers the location of the nest until she is ready to lay. In these birds, females perform better on spatial memory tests than males, who do not participate in the nest seeking (1). In two other studies on birds, there were some slight differences in how males and females learned a new spatial memory but overall performance was the same (2, 3). However, there were many outside factors involved in these tasks that could have affected the birds’ ability to learn.
When we look into the world, we see geometry that tells us about the layout of our surroundings. People have spent a lot of time and effort researching how people perceive distance and scale. An important tool that is often used to this perception is virtual reality (VR). However, VR has its own limitations that affect people’s perceptions and actions. A common problem is distance compression. This problem causes people to perceive their surroundings to be closer to them than they actually are, essentially making the world look smaller. Most space perception research in VR has focused on this topic. However, we see more than just distances. We also see orientations or angular relationships between objects. Very little work has examined whether or not orientation perception is similarly affected by VR. The work that we talked about in our presentation was the first study to investigate this area.