Abstract: AgRP neurons in the hypothalamus play a critical role in shaping the structure and function of the prefrontal cortex in mice. The findings shed light on how the prefrontal cortex is altered in disorders such as schizophrenia.
Source: Yale
The prefrontal cortex region of the human brain is responsible for a number of complex functions, from decision-making to certain types of memory.
When something goes wrong in this part of the brain, it can be very detrimental to cognition and behavior. In fact, prefrontal cortex dysfunction is linked to several psychiatric illnesses, such as schizophrenia and major depressive disorder.
Yale researchers and their colleagues in Hungary have discovered that cells in the hypothalamus, an area of the brain that controls functions such as hunger and body temperature, play an important role in shaping the structure and the function of the prefrontal cortex in mice, a finding that could offer clues about how this region of the brain is altered in the disease and open new avenues for treatment.
They reported their findings July 29 in the journal Molecular Psychiatry.
For the study, the researchers focused on agouti-related peptide (AgRP) neurons located in the hypothalamus region of the brain. These neurons control hunger and regulate both feeding and non-feeding behaviors, such as reward-seeking and offspring-parent bonding, among others.
When the researchers impaired AgRP neurons in mice, they found that there were fewer neurons in the prefrontal cortex than in healthy animals.
“The neurons that remained were smaller than usual and behaved differently in response to cues from the body and signals from surrounding cells,” said Tamas Horvath, the Jean and David W. Wallace of Comparative Medicine at Yale and lead author of the study.
AgRP neurons do not have strong direct connections with the cortex. But they do project to other brain regions that connect to the prefrontal cortex.
Horvath and colleagues found that neurons in one of these areas, a midbrain region known as the ventral tegmental area, were hyperactive when AgRP neurons were impaired. These hyperactive neurons then released more dopamine, a neurotransmitter, into the prefrontal cortex than is typical in healthy mice, which in turn negatively affected the mouse’s behavior.
For example, they found that the mice moved a lot more and had abnormal startle responses.
It makes sense that these neurons that control hunger and feeding affect the cortex and behavior, Horvath says.
“When you’re hungry, you need all your behaviors to be aligned so you can find food and eat it,” he said. “And when you’re no longer hungry, you have to change your behaviors to focus on what’s important in that moment.”
After discovering the effects that impaired AgRP cells had on the cortex, the researchers tried to prevent them. They found that clozapine, a type of antipsychotic that blocks the action of dopamine and is used to treat schizophrenia, was able to prevent some of these problems, including loss of neurons, when given in the right time
When it comes to these cortical changes, Horvath said, timing is crucial. In the study, the impairments began to emerge during puberty, when the brain is still developing and vulnerable. This was also when the administration of clozapine had an impact.
Neurons in the hypothalamus (B) project to the ventral tegmental area (C), where the cells send connections to the prefrontal cortex (A). Through this pathway, AgRP cells in the hypothalamus affect cortical structure and function. Credit: Yale University
“And that tells us that if you mess with homeostatic functions in that specific time period, for example by dieting or overeating, you can have long-lasting effects on your cortical functions,” he said.
The importance of this developmental period may shed light on psychiatric illness, which can often emerge in late adolescence, and why substance use during this time can have lasting effects on behavior, physiology, and disease. .
These findings may also provide a new target for treatment. AgRP cells in the hypothalamus are located outside the blood-brain barrier, a feature of the brain that protects it from harmful substances and prevents many drugs from reaching brain tissue.
“This means that these cells are readily available for intervention,” Horvath said. “Perhaps they can be exploited to alter disorders of higher brain regions.”
The study also adds to a growing body of evidence that cortical function is influenced by more primitive regions of the brain and other parts of the body. Horvath recently demonstrated how AgRP cells can also affect the cortex by mediating the liver.
“The fundamental message here is that in the brain there is very diffuse communication through different pathways,” Horvath said.
See also
“Primitive areas such as the hypothalamus influence higher cortical regions through countless communications, which include brain processes, but also peripheral tissues.
“Let’s go back to the debate between Camillo Golgi and Ramón y Cajal, who shared the Nobel Prize in 1906, but they disagreed on the principles of how the brain works. Our results seem to support Camillo Golgi’s forgotten arguments.”
About this neuroscience research news
Author: Mallory LocklearSource: YaleContact: Mallory Locklear – YaleImage: Image credited to Yale
Original research: Open access. “AgRP neurons control the structure and function of the medial prefrontal cortex” by Bernardo Stutz et al. Molecular Psychiatry
Summary
AgRP neurons control the structure and function of the medial prefrontal cortex
Hypothalamic agouti-related neuropeptide Y (AgRP)-expressing neurons play a critical role in both feeding and non-feeding behaviors in infant, adolescent, and adult mice, suggesting their broad modulatory impact in brain functions.
Here we show that constitutive impairment of AgRP neurons or their peripuberal chemogenetic inhibition resulted in both numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice.
These changes were accompanied by altered oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by administration of clozapine, a non-selective γ-receptor antagonist. dopamine The observed AgRP effects are transduced to mPFC in part by dopaminergic neurons in the ventral tegmental area and may also be transmitted by medial thalamic neurons.
Our results unmasked a previously unsuspected role of hypothalamic AgRP neurons in controlling neural pathways that regulate higher-order brain functions during development and adulthood.