Transcriptomic Characterization of the Human Insular Cortex and Claustrum

Abstract

The insular cortex has been linked to a multitude of functions. In contrast, the nearby claustrum is a densely connected subcortical region with unclear function. To view the insula-claustrum region from the molecular perspective we analyzed the transcriptomic profile of these areas in six adult and four fetal human brains. We identified marker genes with specific expression and performed transcriptome-wide tests for enrichment of biological processes, molecular functions, and cellular components. In addition, specific insular and claustral expression of genes pertaining to diseases, addiction, and depression was tested. At the anatomical level, we used brain-wide analyses to determine the specificity of our results and to determine the transcriptomic similarity of the insula-claustrum region. We found UCMA to be the most significantly enriched gene in the insular cortex and confirmed specific expression of NR4A2, NTNG2, and LXN in the claustrum. Furthermore, the insula was found to have enriched expression of genes associated with mood disorders, learning, cardiac muscle contraction, oxygen transport, glutamate and dopamine signaling. Specific expression in the claustrum was enriched for genes pertaining to human immunodeficiency virus (HIV), severe intellectual disability, epileptic encephalopathy, intracellular transport, spine development, and macroautophagy. We tested for enrichment of genes related to addiction and depression, but they were generally not highly specific to the insula-claustrum region. Exceptions include high insular expression of genes linked to cocaine abuse and genes associated with ever smoking in the claustrum. Brain-wide, we find that markers of the adult claustrum are most specifically expressed in the fetal and adult insula. Altogether, our results provide a novel molecular perspective on the unique properties of the insula and claustrum.

The mystery of claustral neural circuits and recent updates on its role in neurodegenerative pathology

“…Analysis of specific genetic markers in the insular cortex and the claustrum show different genetic profiles, which underlines the separate ontogeny of these structures [ 61 ]. Interestingly, despite specific genetic profile differences between the insular cortex and the claustrum, these two areas have the most similarities in genetic expression, compared to the rest of the brain regions [ 61 ]. Nonetheless, existing data suggests that the claustrum is an independent ontological structure, characteristic of newer and advanced neural function development.…”

“…A transcriptome-wide analysis of claustrum neural cell component provides the most specific differentiation of specific cellular profiles. As such, NR4A2 , NTNG2 , and LXN are thought to be more strongly expressed in the claustrum [ 61 ]. Furthermore, the specific expression patterns in the claustrum show enriched genes pertaining to severe intellectual disability, epileptic encephalopathy, intracellular transport, spine development, macroautophagy, smoking addiction.…”

“…Furthermore, the specific expression patterns in the claustrum show enriched genes pertaining to severe intellectual disability, epileptic encephalopathy, intracellular transport, spine development, macroautophagy, smoking addiction. The NR4A2 gene plays a role in dopamine regulation, and has been implicated in depression, drug addiction, Parkinson’s disease, schizophrenia and bipolar disorder [ 61 ].…”

“…The claustrum has also been shown to participate in memory storage, contiguity learning, suppression of natural urges, psychoses and recognition of fear [ 61 – 63 ]. The theory of the claustrum acting as a cortical-cortical relay center that supports attention is of significance [ 6 ].…”

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

“…Similarly, the claustrum has also been implicated in many neuropsychiatric disorders: claustral volume is smaller in humans with bipolar disorder (Selvaraj et al, 2012 ), depression and schizophrenia (Bernstein et al, 2016 ). The human claustrum also expresses depression-related genes (Ibrahim et al, 2019 ) and its activity is altered across multiple neuropsychiatric disorders (Farruggia et al, 2020 ). Moreover, the claustrum has been implicated in anxiety (Smith et al, 2019b ; Niu et al, 2020 ).…”