summary: Anhedonia and depression arise when POMC neurons in the arcuate nucleus of the hypothalamus become overactive as a result of chronic stress. Reducing activity also reduces feelings of depression and loss of pleasure.
Source: Medical College of Georgia, Augusta University
It is clear that chronic stress can affect our behavior, leading to problems such as depression, reduced interest in things that once brought us pleasure, even post-traumatic stress disorder.
Now scientists have evidence that a group of neurons in an arc-shaped part of the brain becomes overactive after chronic exposure to stress. When these POMC neurons become overactive, this type of behavioral problem results and when the scientists reduce their activity, it reduces the behaviours, they report in the journal. Molecular Psychiatry.
Scientists at the Medical College of Georgia at Augusta University looked at the hypothalamus, which is key to functions such as secreting hormones and regulating hunger, thirst, mood, sex drive, and sleep, at a group of neurons called proopiomelanocortin, or POMC, neurons, in response. To 10 days of chronic, unpredictable stress.
Unexpected chronic stress is used extensively to study the effect of stress exposure in animal models, and in this case it included things like restraint, prolonged wet bedding in a tilted cage, and social isolation.
They found that stressors increased the spontaneous firing of these POMC neurons in male and female rats, says corresponding author Xin Yun Lu, MD, PhD, chair of the MCG Division of Neuroscience and Regenerative Medicine and Georgia Distinguished Researcher in Translational Neuroscience.
When they activated neurons directly, rather than letting stress increase their firing, it also led to a pronounced inability to feel pleasure, which is called anhedonia, and behavioral hopelessness, which is basically depression.
In humans, indicators of anhedonia may include not interacting with good friends and loss of libido.
In rats, their usual love for sugar water, and male rats, who usually like to sniff the urine of females when they are in heat, also lose some interest.
Conversely, when the MCG scientists inhibited neuronal firing, it reduced these types of stress-induced behavioral changes in both sexes.
The findings suggest that POMC neurons are “both necessary and sufficient” for increased susceptibility to stress, and that their increased firing is a driver of resulting behavioral changes such as depression. In fact, stress overtly reduced inhibitory inputs to POMC neurons, says Lu.
POMC neurons are located in the arcuate nucleus, or ARC, of the hypothalamus, an arc-shaped brain region already thought to be important for how chronic stress affects behavior.
The same area was occupied by another group of neurons, called AgRP neurons, that are important for resistance to chronic stress and depression, Lu and her team reported in the paper. Molecular Psychiatry In early 2021.
In the face of chronic stress, Lu’s lab reported that AgRP activation decreases along with behavioral changes such as anhedonia, and that when they stimulate those neurons, the behaviors decrease. Her team also wanted to find out what chronic stress was doing to POMC neurons.
AgRP neurons, known for their foraging role when we feel hungry, are known to have a yin-and-yang relationship with POMC neurons: when AgRP activation goes up, for example, POMC activation goes down.
“If you stimulate AgRP neurons, it can lead to immediate and powerful feedback,” says Lu. Food deprivation also increases the firing of these neurons. It is also known that when triggered by hunger signals, AgRP neurons send messages directly to POMC neurons to release the brakes upon feeding.
Their studies found that chronic stress disrupts the balance of yin and yang between these two groups of neurons. Although projection of AgRP on POMC neurons is clearly important for firing activity, the intrinsic mechanism is probably the main mechanism underlying overactivation of POMC neurons by chronic stress, says Lu.
The intrinsic mechanism may involve potassium channels in POMC neurons that are known to respond to a range of different signals and, upon opening, lead to an influx of potassium from the cell, dampening neuronal excitation.
While the possible role of these potassium channels in POMC neurons in response to stress needs, the scientists suspect that stress also affects potassium channels and that opening these channels might be a potential targeted therapy to suppress POMC neurons.
It is also known that excessive activity of nerve cells leads to seizures, and there are anticonvulsants given to open potassium channels and reduce excessive firing. There’s even some early clinical evidence that these drugs may also be helpful in treating depression and anhedonia, and what Lu’s lab found may help explain why.
Lu hasn’t looked yet, but wants to further explore the role of these channels to better understand how stress affects them in POMC neurons and how best to target the channels if their findings continue to indicate that they play a key role in POMC excitatory neurons.
Chronic stress affects all body systems, according to the American Psychological Association. Even the muscles tense to keep us on guard against injury and pain. Stress can cause shortness of breath, especially in those with pre-existing respiratory problems such as asthma. In the long run, it can increase your risk of high blood pressure, heart attack, and stroke, and even change the good bacteria in our gut that help us digest food.
Funding: The research was funded by the National Institutes of Health.
About this stress and neuroscience research news
author: Tony Baker
Source: Medical College of Georgia, Augusta University
Contact: Tony Baker – Augusta University College of Medicine of Georgia
picture: The image is in the public domain
Original search: open access.
“Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits” by Xin-Yun Lu et al. Molecular Psychiatry
Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits.
Exposure to chronic stress leads to maladaptive behavioral responses and increases susceptibility to neuropsychiatric conditions. However, specific neuronal groups and circuits that are highly sensitive to stress and lead to maladaptive behavioral responses remain to be identified.
Here we investigate patterns of spontaneous activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus after exposure to chronic unanticipated stress (CUS) for 10 days, a stress paradigm used to induce behavioral deficits such as anhedonia and anhedonia. Despair.
CUS exposure increased spontaneous firing of POMC neurons in both male and female mice, which was attributed to decreased GABA-mediated synaptic inhibition and increased excitability of intrinsic neurons.
While acute activation of POMC neurons failed to induce behavioral changes in unstressed rats of both sexes, repeated subacute (3 days) and chronic (10 days) activation of POMC neurons was sufficient to induce behavioral anhedonia and despair in males but not subacute females. . non-stress conditions.
Acute activation of POMC neurons enhanced susceptibility to subthreshold unexpected stress in both male and female rats. Conversely, acute inhibition of POMC neurons was sufficient to reverse CUS-induced anhedonia and behavioral despair in both sexes.
Collectively, these results indicate that chronic stress leads to synaptic and intrinsic plasticity of POMC neurons, leading to neuronal hyperactivity. Our findings indicate that dysfunction in POMC neurons results in chronic stress-related behavioral deficits.
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