Unraveling the Mysteries of Psychological Loss: A Deep Dive into Molecular Mechanisms and Their Behavioral Consequences



Whether it’s the loss of a cherished relationship, financial stability, secure housing, or even one’s health, the impact of such losses can be profoundly detrimental to one’s well-being and overall quality of life [1,2,3].

This phenomenon is especially pronounced during times of natural disasters, political turmoil, and global pandemics, which disrupt the normal rhythms of life and intensify feelings of loss and uncertainty [4].

Psychological loss can be defined as the emotional, cognitive, and behavioral responses to the perceived deprivation or absence of something or someone significant. It extends beyond the loss of life and encompasses various domains of human existence, including:

  • Loss of a Loved One: The most widely recognized form of psychological loss is the death of a family member, friend, or close acquaintance. This type of loss often leads to grief, which is a natural response to the emotional emptiness left behind.
  • Loss of Identity: Significant life changes such as retirement, divorce, or a major career shift can lead to a loss of identity. When one’s sense of self is intertwined with a particular role or status, letting go of that identity can be deeply challenging.
  • Loss of Health: Suffering from a debilitating illness or experiencing a chronic health condition can result in profound psychological loss. Individuals may mourn the loss of their former physical capabilities and the life they once knew.
  • Loss of Relationships: The end of a romantic relationship, the dissolution of a friendship, or estrangement from family members can bring about a deep sense of loss, often accompanied by feelings of rejection or abandonment.
  • Loss of Dreams and Aspirations: Unfulfilled dreams, failed goals, or missed opportunities can lead to a sense of loss. This form of psychological loss is closely tied to the grief of unmet expectations.

Psychological Processes of Psychological Loss

  • Denial and Shock: When confronted with a significant loss, individuals often enter a state of shock and denial. This initial phase serves as a protective mechanism, allowing the mind to gradually process the reality of the loss.
  • Anger and Bargaining: As the shock wears off, anger and bargaining may emerge. Individuals may experience anger towards themselves, others, or even the departed, searching for ways to reverse or alleviate the loss.
  • Depression and Sadness: Deep sadness and depression are common responses to psychological loss. This phase involves coming to terms with the irreversibility of the loss and the emotional pain it entails.
  • Acceptance and Adjustment: In time, individuals may reach a stage of acceptance, where they learn to live with the loss. This does not necessarily mean they have completely moved on but rather that they have integrated the loss into their life story.

Impact of Psychological Loss

Psychological loss can have profound and lasting effects on individuals:

  • Emotional Impact: Grief, sadness, anger, and guilt are just some of the emotions that accompany psychological loss. These emotions can be intense and enduring, affecting one’s mental well-being.
  • Physical Effects: The stress and emotional turmoil associated with psychological loss can manifest physically, leading to sleep disturbances, fatigue, and even compromised immune function.
  • Cognitive Changes: Loss can disrupt cognitive functioning, leading to difficulties in concentration, memory, and decision-making.
  • Social Consequences: Loss often affects one’s social life, potentially leading to social withdrawal or strained relationships with others who may not fully understand or empathize with the grieving process.
  • Spiritual and Existential Questions: Loss can prompt individuals to question the meaning of life, their place in the world, and their beliefs and values.

Defining Psychological Loss

Psychological loss can be understood as a “state of deprivation of a motivationally significant conspecific, object, or situation” [1]. It triggers a complex array of emotional responses that closely resemble the symptoms of major depressive disorder (MDD), including amotivation, sadness, withdrawal, and rumination [1,2,3].

Interestingly, loss can also manifest with atypical MDD symptoms such as weight gain and a hypoactive hypothalamic–pituitary–adrenal (HPA) axis responsivity [5,6]. Despite its prevalence and far-reaching consequences, the molecular mechanisms underlying psychological loss remain poorly understood.

This is partly because the unique phenotypic characteristics associated with loss are challenging to clinically track and have received limited attention in preclinical research [5,6,7]. Therefore, delving into the molecular mechanisms that drive the response to loss could potentially uncover innovative treatments with broad applications.

A Novel Rat Model for Investigating Psychological Loss

Recent advancements in the field have led to the development of a rat model for studying psychological loss, which has opened up exciting avenues for research [8, 9]. In this model, environmental enrichment (EE) serves as a proxy for positive life experiences, while the removal of EE serves as an emulation of loss [8, 9].

EE is known to have rewarding properties in rodents, providing them with social, physical, and cognitive stimulation that enhances cognition and neuroplasticity while reducing emotional reactivity to stress [10, 11]. The enrichment removal (ER) protocol involves transitioning rats from 4 weeks of EE to single housing devoid of positive stimuli.

This drastic shift from a highly stimulating environment to a less stimulating one mirrors the experience of losing something of significant value. Notably, adult male rats subjected to ER display a range of “loss-like” behaviors after just one week, including increased passive coping in the forced swim test, heightened hedonic drive in the sucrose preference test, weight gain, and a hypoactive HPA axis response compared to rats in EE and standard housing conditions [8]. Consequently, ER offers a unique opportunity to investigate the pathologies associated with loss in a rodent model.

Investigating the Biological Substrates of Psychological Loss

To gain insights into the biological substrates of psychological loss, researchers have employed a combination of approaches, including post-behavior Fos expression analysis and multi-omics techniques [12,13,14]. Fos expression analysis revealed the selective activation of the basolateral amygdala (BLA) following ER, a brain region known for its roles in stress regulation and behavioral adaptation [12,13,14]. This marked the BLA as a key player in the response to loss.

Multi-omics approaches, which encompass a range of data from multiple cohorts and platforms, have been instrumental in building molecular signatures of ER in the BLA [15,16,17]. Bioinformatics analyses of these signatures have consistently pointed towards microglia, the resident immune cells in the brain, and the extracellular matrix (ECM), a crucial scaffolding that supports synaptic development and plasticity [18,19,20].

Both microglia and ECM have intricate relationships with stress, making them intriguing candidates for further investigation [18,19,21,22]. Subsequent molecular and behavioral studies have shed light on how ER-induced alterations in these candidate mechanisms affect BLA plasticity and BLA-dependent behaviors.

Microglia and ECM: Unexpected Players in Psychological Loss

ER has been found to reduce the size, complexity, and phagocytic activity of BLA microglia, suggesting that these microglia may have impaired capacity to survey and interact with their surroundings [15,16,17,21]. While most studies focus on conditions with overly active microglia and neuroinflammation, it’s important to note that a loss of function in microglia can also be detrimental, as these cells play a critical role in regulating neurons and the brain’s microenvironment to maintain homeostasis. Depleting microglia can lead to cognitive, social, and motor impairments [15,16,17,21]. Thus, the reduction in microglia surveillance and phagocytosis observed following ER could potentially hinder the functional capacity of the BLA.

On the other hand, ER has been associated with increased ECM expression and organization, particularly in perineuronal nets (PNNs) that decorate parvalbumin (PV) interneurons [19,35]. These changes in ECM likely indicate decreased plasticity, as PNNs physically impede the formation of new neural connections, making the decorated cells less adaptable [19,35]. Moreover, several PNN-associated changes in PV interneurons suggest greater synaptic efficacy, reduced inhibition, and increased PV activity [18,38]. Depleting PNNs has been shown to decrease PV activity and maturity [44,51], supporting the idea that PV cells with PNNs are more active. This aligns with the concept that the BLA becomes more inhibited and less plastic following ER, potentially affecting its capacity to evaluate and select appropriate responses to various stimuli.

Behavioral Consequences of Molecular Changes

The molecular changes in the BLA following ER have important behavioral consequences. The BLA is a crucial neural hub responsible for selecting appropriate behavioral responses to various stimuli by gathering and evaluating sensory and associational information from multiple sources. It assesses the salience and valence of these inputs and signals downstream regions to execute appropriate responses [12,13,14,52,53]. Reduced plasticity and increased inhibition in the BLA, as observed after ER, can disrupt its ability to evaluate and select responses to stimuli. This leads to exaggerated responses to some stimuli, such as heightened startle reactions, and blunted responses to others, like those requiring fear conditioning [12,13,14].

For instance, startle responses may be intensified due to increased BLA inhibition, causing an inability to effectively filter responses to relatively low-salience threats. Conversely, responses to high-salience threats, which necessitate behaviors like freezing or social avoidance, may be dampened. These findings are consistent with previous studies showing that depleting BLA ECM increases behavioral flexibility and adaptability [20,34]. To further validate this relationship, researchers have experimentally depleted BLA PNNs during the removal period, successfully rescuing several ER physiological and behavioral phenotypes. This intervention attenuated weight gain and blocked enhanced avoidance, startle reactions, and passive coping, supporting the notion that BLA PNN accumulation is instrumental in driving behavior following ER.

Future Directions and Considerations

It’s worth noting that this study primarily focused on male rats due to distinct differences observed in preliminary RNAseq data. While male rats exhibited clear implications of BLA immune and extracellular pathways in ER, females displayed more significant dysregulation in metabolic, developmental, and hormonal pathways. This suggests that there may be gender-specific mechanisms at play in the experience of psychological loss, warranting further research [9].

Additionally, the choice of the EE group as a control for these studies is essential, as it shares the experiential aspect that is removed during ER. It’s essential to recognize that the transition from EE to ER does not simply revert endpoints to standard housing levels, as evidenced by the distinct ER behavioral and molecular phenotypes that differ from both standard housing and EE controls. This underscores that loss represents a unique state characterized by the withdrawal of multiple positive stimuli, and the microglia/ECM phenotypes studied here play a pivotal role in this process.


Psychological loss is a universal human experience with far-reaching consequences for emotional well-being and adaptability. This deep dive into the molecular mechanisms and behavioral consequences of loss, using a novel rat model, has revealed the importance of the basolateral amygdala (BLA), microglia, and the extracellular matrix (ECM) in the response to loss. ER-induced changes in these mechanisms impact BLA plasticity and behavior, leading to heightened responses to some stimuli and blunted reactions to others.

Targeting BLA PNNs offers promise as a potential intervention to ameliorate loss symptoms, offering hope for those grappling with the emotional rigidity and impaired adaptability that often accompany psychological loss. Ultimately, advancing our understanding of the neurobiology of loss will be crucial in developing effective interventions for mitigating its widespread impact on mental health and overall well-being.

reference link : https://www.nature.com/articles/s41380-023-02231-8#Sec1


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