When chronic stress activates these neurons, behavioral problems like loss of pleasure and depression result.

Summary: Anhedonia and depression occur 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: Georgia Medical College at Augusta University

It’s clear that chronic stress can impact our behavior, leading to issues like depression, reduced interest in things that once gave us pleasure, and even PTSD.

Scientists now have evidence that a group of neurons in an arc-shaped part of the brain become overactive 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 behaviors, they report in the journal Molecular psychiatry.

Scientists from the Medical College of Georgia at Augusta University have looked into the hypothalamus, key to functions such as the release of hormones and the regulation of hunger, thirst, mood, libido and sleep, a population of neurons called proopiomelanocortin, or POMC, neurons, in response to 10 days of chronic, unpredictable stress.

Unpredictable chronic stress is widely used to study the impact of stress exposure in animal models, and in this case it included things like restraint, prolonged wet litter in a tilted cage, and social isolation.

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

When they fired neurons directly, rather than letting stress increase their firing, it also led to an apparent inability to feel pleasure, called anhedonia, and behavioral hopelessness, which is basically depression.

In men, indicators of anhedonia could include stopping interaction with good friends and loss of libido.

In mice, their usual love for sugar water disappears, and male mice, which normally enjoy sniffing female urine when in heat, also lose some interest.

Conversely, when the MCG scientists inhibited neuron firing, 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 their increased firing is a driver of resultant behavioral changes like depression. In fact, stress overtly decreased inhibitory inputs to POMC neurons, Lu says.

POMC neurons are found 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.

Occupying the same region is another population of neurons, called AgRP neurons, that are important for resilience to chronic stress and depression, Lu and his team reported in Molecular psychiatry early 2021.

In the face of chronic stress, Lu’s lab reported that AgRP activation decreases as behavioral changes like anhedonia occur, and when they stimulate these neurons, behaviors decrease. His team also wanted to know what chronic stress does to POMC neurons.

AgRP neurons, best known for their role in finding food when we are hungry, are known to have a yin-yang relationship with POMC neurons: when AgRP activation increases, for example, activation of POMC decreases.

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

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When they fired neurons directly, rather than letting stress increase their firing, it also led to an apparent inability to feel pleasure, called anhedonia, and behavioral hopelessness, which is basically depression. Image is in public domain

Their studies 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 gating activity, the intrinsic mechanism is likely the primary mechanism underlying the hyperactivity of POMC neurons by chronic stress, Lu says.

The intrinsic mechanism may include potassium channels in POMC neurons that are known to respond to a range of different signals and, when open, lead to potassium outflow from the cell, which dampens neuronal excitation.

While the potential role of these potassium channels in POMC neurons in response to stress requires study, scientists suspect that stress also affects potassium channels and that opening these channels could be a possible targeted therapy to restrict neurons POMC that fire wildly.

Excessive activity of neurons is also known to produce seizures and there are anticonvulsants given to open the potassium channels and decrease this excessive discharge. There’s even early clinical evidence that these drugs might also be helpful in treating depression and anhedonia, and what Lu’s lab finds may help explain why.

Lu hasn’t watched yet, but she 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 role. key in the excitation of POMC neurons. .

Chronic stress affects every system in the body, according to the American Psychological Association. Even the muscles tense to guard our guard against injury and pain. Stress can cause shortness of breath, especially in people with pre-existing breathing problems like asthma. In the longer term, it can increase the risk of high blood pressure, heart attack and stroke, and even impair the good bacteria in our gut that help us digest food.

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

About this news about stress and neuroscience research

Author: Tony Boulanger
Source: Georgia Medical College at Augusta University
Contact: Toni Baker – Medical College of Georgia at Augusta University
Picture: Image is in public domain

Original research: Free access.
“The increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits” by Xin-Yun Lu et al. Molecular psychiatry


Summary

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

Chronic exposure to stress induces maladaptive behavioral responses and increases susceptibility to neuropsychiatric disorders. However, specific neural populations and circuits that are highly sensitive to stress and trigger maladaptive behavioral responses remain to be identified.

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

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

While acute activation of POMC neurons failed to induce behavioral changes in unstressed mice of both sexes, repeated subacute (3 days) and chronic (10 days) activation of POMC neurons was sufficient to induce anhedonia and behavioral despair in males but not in females under non-stress conditions.

Acute activation of POMC neurons promoted subthreshold unpredictable stress sensitivity 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 results suggest that dysfunction of POMC neurons leads to chronic stress-related behavioral deficits.

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