When chronic stress activates these neurons, behavioral problems such as loss of pleasure and depression arise

Overview: Anhedonia and depression develop when POMC neurons in the arcuate nucleus of the hypothalamus become hyperactive due to chronic stress. Reducing activity also reduces feelings of depression and loss of pleasure.

Source: Medical College of Georgia at Augusta University

Clearly, chronic stress can affect our behavior, leading to problems such as depression, decreased interest in things that used to bring us pleasure, even PTSD.

Now scientists have evidence that a group of neurons in an arcuate part of the brain become hyperactive after chronic exposure to stress. When these POMC neurons become super-active, these kinds of behavioral problems result, and when scientists reduce their activity, it reduces behavior, they report in the journal Molecular Psychiatry.

Scientists at the Medical College of Georgia at Augusta University looked inside the hypothalamus, key to functions such as releasing hormones and regulating hunger, thirst, mood, sex drive and sleep, at a population of neurons that secrete proopiomelanocortin, or POMC neurons. are called. up to 10 days of chronic, unpredictable stress.

Chronic unpredictable stress is widely used to study the impact of stress exposure in animal models, and in this case that included things like restraint, prolonged wet bedding in a tilted cage, and social isolation.

They found that the stressors increased the spontaneous firing of these POMC neurons in male and female mice, says corresponding author Xin-Yun Lu, MD, PhD, chair of the MCG Department of Neuroscience and Regenerative Medicine and Georgia Research Alliance Eminent Scholar in Translational Neuroscience.

When they activated the neurons directly, rather than letting stress increase their firing, it also resulted in the apparent inability to feel pleasure, called anhedonia, and behavioral desperation, which is essentially depression.

In humans, indicators of anhedonia can include no longer associating with close friends and a loss of libido.

In mice, their habitual love of sugar water diminishes, and male mice, who normally like to sniff females’ urine when in heat, also lose some of their interest.

Conversely, when the MCG scientists inhibited the firing of the neurons, it reduced these kinds of stress-induced behavioral changes in both sexes.

The results indicate that POMC neurons are “both necessary and sufficient” to increase susceptibility to stress, and that their increased firing is a driver of resulting behavioral changes such as depression. In fact, stress overtly reduced inhibitory input on POMC neurons, Lu says.

The POMC neurons are located in the arcuate nucleus, or ARC, of ​​the hypothalamus, an arcuate brain region already thought to be important for how chronic stress affects behavior.

The same region is home to another population of neurons called AgRP neurons, which are important for resilience to chronic stress and depression, Lu and her team reported in Molecular Psychiatry early 2021.

In the face of chronic stress, Lu’s lab reported that AgRP activation decreases as behavioral changes such as anhedonia occur, and that when they stimulated those neurons, the behavior decreased. Her team also wanted to know what chronic stress does to the POMC neurons.

AgRP neurons, better known for their role in our search for food when we are hungry, are known to have a yin-yang relationship with POMC neurons: when AgRP activation goes up, for example, POMC- activation down.

“If you stimulate AgRP neurons, it can trigger immediate, robust feeding,” says Lu. Food deprivation also increases the firing of these neurons. It is also known that AgRP neurons, when excited by hunger signals, send direct messages to the POMC neurons to release the brakes on feeding.

When they activated the neurons directly, rather than letting stress increase their firing, it also resulted in the apparent inability to feel pleasure, called anhedonia, and behavioral desperation, which is essentially depression. The image is in the public domain

Their studies found that chronic stress disrupts the yin-yang balance between these two neuronal populations. While the projection of AgRP onto POMC neurons is clearly important for their firing activity, the intrinsic mechanism is likely the most important mechanism underlying hyperactivity of POMC neurons from 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 when open lead to potassium flowing out of the cell, dampening neuronal excitation.

While the potential role of these potassium channels in POMC neurons in response to stress needs to be explored, the scientists suspect that stress also affects potassium channels, and that opening those channels could be a potential targeted treatment to stimulate the wild-firing POMC neurons in to keep under control.

Excessive activity of neurons is also known to cause seizures and anticonvulsants are given to open potassium channels and reduce that excess firing. There’s even some early clinical evidence that these drugs may also be helpful in treating depression and anhedonia, and what the Lu lab finds may help explain why.

Lu hasn’t looked yet, but she wants to further investigate 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 exciting POMC neurons.

According to the American Psychological Association, chronic stress affects all body systems. Even muscles tense to keep us wary of injury and pain. Stress can cause shortness of breath, especially in people with pre-existing breathing problems such as asthma. In the longer term, it can increase the risk of hypertension, heart attack and stroke, and even alter the good bacteria in our gut that help us digest food.

Also see

This shows a diagram from the study

financing: The research was funded by the National Institutes of Health.

About this stress and neuroscience research news

Writer: Tony Baker
Source: Medical College of Georgia at Augusta University
Contact: Toni Baker – Medical College of Georgia at Augusta University
Image: The image is in the public domain

Original research: 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


Abstract

Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits

Chronic exposure to stress causes maladaptive behavioral responses and increases susceptibility to neuropsychiatric disorders. However, specific neuronal populations and circuits that are highly sensitive to stress and elicit maladaptive behavioral responses have yet to be identified.

Here we investigate the patterns of spontaneous activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus after exposure to chronic unpredictable stress (CUS) for 10 days, a stress paradigm used to address behavioral deficits such as anhedonia and conduct disorder. wake up. despair.

CUS exposure increased the spontaneous firing of POMC neurons in both male and female mice, attributable to decreased GABA-mediated synaptic inhibition and increased intrinsic neuronal excitability.

Although acute activation of POMC neurons did not cause behavioral changes in non-stressed mice of either sex, subacute (3 days) and chronic (10 days) repeated activation of POMC neurons was sufficient to cause anhedonia and behavioral despair in males, but not in males. females. non-stressful conditions.

Acute activation of POMC neurons promoted susceptibility to below-threshold unpredictable stress in both male and female mice. 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 induces both synaptic and intrinsic plasticity of POMC neurons, leading to neuronal hyperactivity. Our findings suggest that POMC neuron dysfunction causes chronic stress-related behavioral deficits.

When chronic stress activates these neurons, behavioral problems such as loss of pleasure and depression arise

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