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Herman says, unfortunately, that loss is a major contributor to several mental health related conditions. Credit: Neuroscience News

Brain’s Molecular Response to Psychological Loss

Summary: Psychological loss, be it from job loss or the death of a loved one, affects well-being immensely, yet its molecular mechanism in the brain remains enigmatic. Researchers utilized the method of enrichment removal (ER) to discern these elusive processes. The study spotlighted a specific brain area central to psychological loss and unveiled potential molecular targets to mitigate its adverse effects.

Key Facts:

  1. The University of Cincinnati’s research delves into the brain’s molecular processes associated with psychological loss.
  2. Using enrichment removal (ER) on animal models, the study discerned an overactivity in a brain region linked to stress regulation and behavioral adaptation after a loss.
  3. The research highlights not the neurons, but their insulating cells, as the root cause, marking a groundbreaking revelation.

Source: University of Cincinnati

Psychological loss can occur when someone loses a job, loses a sense of control or safety or when a spouse dies. Such loss, which erodes well-being and negatively impacts quality of life, may be a common experience but little is known about the molecular process in the brain that occurs because of loss.

New research from the University of Cincinnati explores those mechanisms through a process known as enrichment removal (ER). The study highlights an area of the brain that plays a key role in psychological loss and identifies new molecular targets that may alleviate its impact.

The research was published in the journal Molecular Psychiatry.

The research was led by Marissa Smail, a graduate student in the Department of Pharmacology and Systems Physiology at the UC College of Medicine. She says she’s always been interested in the mechanics underlying psychiatric disorders, in particular what molecular changes happening in the brain make certain symptoms emerge and how those mechanisms can be used to alleviate debilitating conditions.  

“Most research in this field focuses on disorders such as depression and PTSD — very worthy causes but not nearly as common as loss,” Smail says.

“We have all lost something and experienced the negative impact of that loss at some point. Using ER to understand the mechanisms driving this extremely common experience is a great question that not only sheds light on how we interact with the world but also has the potential to reveal novel therapeutic targets that may be of widespread benefit.”

The research examined animal models which were provided with an environment that gave them the opportunity to climb and explore and enjoy a communal experience of various toys and shelters for four weeks.

The ER subjects were then removed from that environment for an extended period (one month) and researchers used a screen of the brain to look at the impact on the region of the brain with established roles in stress regulation and behavioral adaptation following enrichment removal.

“What appears to happen is that in this key area of brain, the support system becomes overactive,” says James Herman, PhD, associate director of the UC Gardner Neuroscience Institute, and Department Chair and the Flor van Maanen Endowed Chair for Pharmacology and Systems Physiology in the UC College of Medicine and senior author of the study.

“Rather than being very [adaptable], and being able to be changed, being able to profit from experience, what ends up happening is the neurons become insulated. As a consequence of that insulation, they’re not able to drive the adaptive behaviors that you would normally see on an everyday basis. It’s not the neurons, it’s the insulators of the neurons that are causing this problem and that’s a very novel finding.”

Herman says, unfortunately, that loss is a major contributor to several mental health related conditions. It’s frequently a trigger for depressive episodes and may contribute to the epidemic of mental health consequences linked to isolation during the COVID-19 pandemic.

Smail says one aspect of the research that she likes is that it is very interdisciplinary and collaborative, and it allowed her to explore a variety of topics and techniques to ultimately identify a novel mechanism that occurs in loss. 

“Beginning with an unbiased screen meant that this was a true ‘follow the data’ project,” Smail says. “We did not expect to investigate the brain’s immune cells and supporting structure, respectively, but these endpoints led to several great collaborations and a range of molecular and behavioral experiments to understand their roles. 

“The resulting mechanism described in the paper is quite novel and shares several characteristics with loss in humans, leading us to believe it is relevant for understanding this common experience.”

About this neuroscience and psychology research news

Author: Bill Bangert
Source: University of Cincinnati
Contact: Bill Bangert – University of Cincinnati
Image: The image is credited to Neuroscience News

Original Research: Open access.
Molecular neurobiology of loss: a role for basolateral amygdala extracellular matrix” by Marissa Smail et al. Molecular Psychiatry


Molecular neurobiology of loss: a role for basolateral amygdala extracellular matrix

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an environmental enrichment removal (ER) paradigm in male rats.

The basolateral amygdala (BLA) was identified as a region of interest, demonstrating differential Fos responsivity to ER and having an established role in stress processing and adaptation. A comprehensive multi-omics investigation of the BLA, spanning multiple cohorts, platforms, and analyses, revealed alterations in microglia and the extracellular matrix (ECM).

Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition within the BLA following loss.

Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, leading to a mismatch between stimulus and reaction intensity.

These loss-like behaviors could be rescued by depleting BLA ECM during the removal period, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.

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