It is clear that chronic stress can affect our behavior, leading to problems such as depression, reduced interest in things that used to bring us pleasure, even post-traumatic stress disorder.
Scientists now have evidence that a group of neurons in the arcuate part of the brain becomes hyperactive after chronic exposure to stress. When POMC neurons become overactive, these behavioral problems occur, and when the scientists reduce their activity, this reduces the behavior, they report in the journal Molecular psychiatry.
Scientists at the Medical College of Georgia at Augusta University examined the hypothalamus, key to functions such as hormone release and the regulation of hunger, thirst, mood, sex drive and sleep, on a population of neurons called propiomelanocortin neurons, or POMCs, in response to up to 10 days chronic, unpredictable stress. Chronic unpredictable stress is widely used to study the effects of stress exposure in animal models, and in this case it involved things like restraint, prolonged wet bed in an inclined cage, and social isolation.
They found that stressors increased the spontaneous firing of these POMC neurons in male and female mice, says corresponding author Xin-Yun Lu, MD, PhD, MCG Chair of Neuroscience and Regenerative Medicine and Research Alliance Distinguished Scientist in Translational Neuroscience Georgia.
When they activated neurons directly, rather than allowing stress to increase their firing, it also led to an apparent inability to experience pleasure, called anhedonia, and behavioral despair, which is essentially depression. In humans, indicators of anhedonia can include not socializing with good friends and loss of libido. In mice, their usual fondness for sugar water wanes, and male mice, who normally enjoy sniffing the urine of females during heat, also lose some of their interest.
In contrast, when the MCG scientists interfered with neuronal activation, it reduced these types of stress-induced behavioral changes in both sexes.
The results show that POMC neurons are “necessary and sufficient” for increased susceptibility to stress, and their increased firing is responsible for subsequent behavioral changes such as depression. In fact, stress clearly reduced the inhibitory actions on POMC neurons, Lu says.
POMC neurons are found in the arcuate nucleus, or ARC, of the hypothalamus, an arcuate region of the brain already thought to be important in how chronic stress affects behavior.
The same region houses another population of neurons called AgRP neurons, which are important for resistance to chronic stress and depression, Lu and her team reported in Molecular psychiatry in early 2021.
In the face of chronic stress, Lu’s lab reported that AgRP activation decreases as behaviors such as anhedonia change, and that when they stimulate these neurons, the behavior decreases. Her team also wanted to know what chronic stress does to POMC neurons.
AgRP neurons, better known for their role in finding food when we are hungry, are known to have a yin-yang relationship with POMC neurons: for example, when AgRP activation increases, POMC activation decreases.
“When you stimulate AgRP neurons, it can trigger immediate, reliable feeding,” Lu says. Food deprivation also increases the firing of these neurons. It is also known that when excited by hunger signals, AgRP neurons send direct messages to POMC neurons to release the feeding brake.
Their research showed that chronic stress disrupts the yin-yang balance between these two neuronal populations. Although the projection of AgRP onto POMC neurons is clearly important for their activation, an intrinsic mechanism is likely the primary mechanism underlying the hyperactivity of POMC neurons due to chronic stress, Lu says.
An intrinsic mechanism may involve potassium channels in POMC neurons, which are known to respond to a number of different signals and, when open, cause potassium to leak out of the cell, reducing neuronal excitability. While the potential role of these potassium channels in POMC neurons in response to stress needs to be explored, scientists suspect that stress also affects potassium channels and that opening these channels may be a possible targeted treatment to curb wildly activated POMC neurons.
Excessive neuronal activity is also known to cause seizures, and there are anticonvulsant drugs designed to open potassium channels and reduce this excessive firing. There’s even some early clinical evidence that these drugs may also be useful in treating depression and anhedonia, and what Lu’s lab is finding may help explain why.
Lu hasn’t looked yet, but she wants to further study the role of these channels to better understand how stress affects them in POMC neurons and how to better target the channels, as their findings continue to show that they play a key role in excitatory POMC neurons.
According to the American Psychological Association, chronic stress affects all body systems. Even muscles tense up to protect themselves from injury and pain. Stress can cause shortness of breath, especially in those who already have respiratory problems such as asthma. In the long term, it can increase the risk of hypertension, heart attack and stroke, and even change the good bacteria in our gut that help us digest food.
The study was funded by the National Institutes of Health.