The Role of Claustral Neurons in Modulating Fentanyl Addiction: Implications for Targeted Interventions


The claustrum is a thin sheet of neurons that lies between the insular and striatal regions of the brain. It has been implicated in various cognitive functions, such as attention, decision making, and consciousness.

However, its role in opioid addiction is largely unknown. In this blog post, we will review some of the recent findings from our lab and others that suggest that the claustrum is a key regulator of opioid intake and reward.

Opioids are a class of drugs that act on opioid receptors in the brain and produce analgesia, euphoria, and dependence. Fentanyl is a synthetic opioid that is 50 to 100 times more potent than morphine and has become a major public health concern due to its widespread illicit use and high risk of overdose.

According to the Centers for Disease Control and Prevention, fentanyl was involved in more than 60% of the opioid-related deaths in the United States in 2020.

One of the brain regions that is affected by opioids is the frontal cortex, which consists of the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC). These regions are involved in executive functions, such as planning, impulse control, and emotional regulation.

Opioids modulate the activity of neurons in the frontal cortex and alter their responses to reward and punishment. For example, chronic opioid exposure reduces the sensitivity of ACC neurons to negative feedback and impairs decision making under uncertainty.

The claustrum is connected to the frontal cortex by bidirectional projections that can either excite or inhibit the activity of frontal neurons. We hypothesized that these claustro-frontal projections play a role in regulating opioid intake and reward by modulating the frontal cortex. To test this hypothesis, we used a combination of techniques, such as single-cell RNA sequencing, fiber photometry, optogenetics, chemogenetics, and electrophysiology, to manipulate and measure the activity of claustral neurons that project to the ACC or OFC in mice that were given access to oral fentanyl solution.

We found that claustral neurons that project to the ACC or OFC have distinct molecular and functional properties. The ACC-projecting neurons express high levels of kappa opioid receptors (KORs), which are activated by endogenous opioids such as dynorphin and mediate aversive effects of opioids.

The OFC-projecting neurons express low levels of KORs but high levels of dopamine receptors, which are activated by dopamine and mediate rewarding effects of opioids. We also found that these two populations of claustral neurons have opposite effects on fentanyl intake and reward. The ACC-projecting neurons inhibit fentanyl intake and reduce fentanyl preference, while the OFC-projecting neurons enhance fentanyl intake and increase fentanyl preference.

These results suggest that the claustrum acts as a gatekeeper of opioid consumption and reward by differentially modulating the activity of the frontal cortex. The ACC-projecting claustral neurons may act as a brake on opioid intake by suppressing the rewarding effects of opioids or enhancing their aversive effects.

The OFC-projecting claustral neurons may act as an accelerator on opioid intake by amplifying the rewarding effects of opioids or attenuating their aversive effects. These findings have important implications for understanding the neural mechanisms underlying opioid addiction and developing novel therapeutic strategies to treat it.

… In deep….

The claustrum, an understudied brain region nestled deep within the cerebral cortex, has long remained a mystery to neuroscientists. Despite its small size, the claustrum’s intricate network of neurons and dense connectivity with various brain regions have piqued the curiosity of researchers, leading to a surge in investigations into its functional significance. This article delves into the fascinating world of claustral neurons, their structural characteristics, connectivity patterns, and emerging research on their role in cognition, consciousness, and neurological disorders. Through an extensive exploration of recent studies, we aim to shed light on the enigmatic claustrum and its potential contributions to our understanding of the human brain.

The claustrum, a thin sheet of gray matter located bilaterally deep within the cerebral cortex, has intrigued neuroscientists for centuries. Initially dismissed as a vestigial structure, recent advancements in neuroimaging techniques and animal studies have rekindled interest in this brain region. This article aims to elucidate the role of claustral neurons, examining their cellular properties and connectivity, and exploring their potential involvement in higher-order brain functions.

Structural Characteristics of Claustral Neurons: Claustral neurons exhibit a remarkable diversity in their morphological and electrophysiological properties. Studies have revealed the presence of multiple subtypes of claustral neurons, each displaying distinct firing patterns, neurotransmitter profiles, and connectivity. This section provides an overview of the structural characteristics of claustral neurons, including their dendritic arborization, axonal projections, and synaptic connectivity.

Connectivity Patterns of the Claustrum: The claustrum is renowned for its extensive connectivity with various cortical and subcortical regions, suggesting its involvement in integrating information across different brain systems. Recent research utilizing viral tracing techniques and optogenetics has unraveled the intricate circuitry of the claustrum, highlighting its bidirectional connections with regions implicated in attention, sensory processing, memory, and emotional regulation. This section examines the connectivity patterns of the claustrum and discusses their implications for information processing and brain-wide communication.

Claustral Neurons and Cognition: While the precise role of the claustrum in cognitive processes remains speculative, recent studies have provided intriguing insights into its potential contributions. Animal models and neuroimaging studies in humans have implicated the claustrum in attentional control, decision-making, and multisensory integration. Furthermore, experimental manipulations of claustral activity have demonstrated modulatory effects on cognitive performance. This section explores the involvement of claustral neurons in cognitive functions and discusses possible mechanisms underlying their influence.

Claustrum and Consciousness: One of the most intriguing hypotheses regarding the claustrum’s function relates to consciousness. Some researchers have proposed that the claustrum acts as a central hub, integrating sensory and cognitive information to generate conscious experiences. Experimental evidence from animal studies and clinical observations in patients with altered consciousness supports this notion. This section explores the theoretical frameworks linking the claustrum to consciousness and highlights ongoing debates surrounding this topic.

Claustrum Dysfunction in Neurological Disorders: Given the claustrum’s extensive connectivity and its involvement in multiple brain functions, it is not surprising that dysfunction in this region has been implicated in several neurological disorders. Studies have implicated the claustrum in schizophrenia, epilepsy, Parkinson’s disease, and autism spectrum disorders. This section reviews the evidence linking claustral abnormalities to these disorders, emphasizing the potential implications for developing novel therapeutic strategies.

Future Directions and Challenges: Despite significant progress in claustrum research, numerous challenges remain. This section discusses the methodological hurdles faced by researchers, including the technical limitations of studying such a small and densely connected brain structure. Additionally, it explores potential future directions, such as advanced imaging techniques, selective manipulation of claustral activity, and computational modeling, which may provide further insights into the functional role of claustral neurons.

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