Insights From Genetic, Neuroimaging, and Behavioral Neuroscience Studies

Mitochondrial dysfunction has been suggested to play a role in the pathophysiology of various neurodegenerative and neuropsychiatric disorders, including autism spectrum disorder (ASD). Kato and colleagues (2) report findings from a PET study in high-functioning adult male subjects with ASD designed to assess brain levels of a key mitochondrial enzyme. Mitochondria are organelles that underlie cellular respiration as they serve to generate energy stores for the cell by facilitating the production of adenosine triphosphate (ATP) via oxidative phosphorylation. When ATP is dephosphorylated to form adenosine diphosphate, usable energy is released; when there is not a demand for energy, ATP stores can be replenished by the phosphorylation of ADP to ATP. In the current study, the authors used the PET ligand ^18FBCPP-EF to assess the amount of binding to the enzyme, mitochondrial electron transport chain complex I. This is a critical enzyme in the mitochondrial electron transport chain, which ultimately results in facilitating the production of ATP. In comparing 23 ASD male subjects not taking psychotropic medications to 24 male control subjects, the results demonstrated a significant reduction in ^18FBCPP-EF binding in the anterior cingulate cortex region of ASD participants. No differences in binding were found in the other brain regions that were examined, which included the superior temporal gyrus, occipital cortex, dorsolateral prefrontal cortex, thalamus, and motor cortex. It is important to note that this finding remained significant when controlling for potential between group differences in brain structure and anxiety and depressive symptoms. Additionally, within the ASD group, individual differences in ^18FBCPP-EF binding potential were negatively correlated with Autism Diagnostic Observation Schedule (ADOS-2) communication scores. While the sample size in this study is small, these initial observations provide in vivo data supporting ASD-related alterations in mitochondrial function in anterior cingulate cortical neurons.

Zwicker and colleagues (3) bring together data from eight different longitudinal studies to assess the combined value of polygenic scores (PGSs) and family history in predicting the development of mood and psychotic disorders. The unique sample used in this study predominantly consisted of offspring of parents that had bipolar disorder, recurrent/chronic major depression, or schizophrenia spectrum disorder. Multiple longitudinal assessments were performed on the offspring of the affected parents, with the first assessment occurring at a mean age of 13.6 years and an average length of follow-up for 5.1 years. Semistructured diagnostic interviews were used to ascertain parents’ diagnoses, and genotyping was performed from offspring DNA to calculate their PGSs. The sample consisted of 1,884 participants, 1,339 of whom were offspring of affected parents. Within the sample, 435 individuals developed a mood or psychotic disorder during the follow-up period. A family history of a mood or psychotic disorder was found to markedly increase offspring risk (hazard ratio=2.82). The PGSs for neuroticism, schizophrenia, depression, ADHD, and the broad psychopathology dimension (p-factor) were also all significantly associated with offspring risk, with the highest hazard ratio of 1.23 found for the neuroticism PGS. In contrast, the PGS for well-being was associated with a significantly reduced risk for offspring to develop mood or psychotic disorders (hazard ratio=0.90). Importantly, when controlling for family history, only the neuroticism and well-being PGS continued to be significantly associated with offspring’s risk, suggesting that, in addition to family history, these PGSs may add value to predict the risk to develop mood or psychotic disorders. In her editorial, Dr. Joanna Biernacka from the Mayo Clinic (4) discusses the interpretation of these findings in relation to methodological issues and other factors that may affect quantitative assessments of the relative value of family history and genetics in predicting risk. She also emphasizes the need to develop PGSs from diverse populations to ensure a deeper understanding of genetic risk. This is important as it will support the development of personalized treatment approaches that are equitable for understudied and marginalized groups.

While autoimmune disorders and psychiatric illnesses are known to be associated with each other, Zeng et al. (5) characterize the extent to which autoimmune and stress-related psychiatric disorders have similar patterns of heritability and shared genetic underpinnings. First, using data from an extremely large Swedish sample of over 4 million individuals, the presence of stress-related disorders (e.g., PTSD, acute stress disorder, and adjustment disorder) and 36 autoimmune disorders was determined. Consistent with other studies, the findings revealed that across the sample, having an autoimmune disorder significantly increased an individual’s probability of also having a stress-related disorder (odds ratio=1.66). By knowing the degree of relatedness of individuals within the sample, familial coaggregation analyses were performed aimed at estimating the likelihood of having both an autoimmune and a stress-related disorder. These analyses demonstrated shared patterns of heritability, i.e., the likelihood of having both an autoimmune disease and a stress-related disorder increased as familial relatedness increased. Next, the investigators used data from over 500,000 participants in the UK Biobank and again demonstrated a significant increased probability for individuals to have both an autoimmune and stress-related disorder. Polygenic risk scores (PRSs) were available from 376,871 UK Biobank participants, which revealed shared genetic underpinnings, albeit small effects, such that polygenic risk scores for autoimmune disorders were associated with stress-related disorders and the PRSs for stress-related disorders were associated with autoimmune diseases. Other analyses demonstrated a significant genetic correlation of 0.26 between autoimmune and stress-related disorders, with the identification of 10 specific genes and five functional gene modules that were shared across these disorders. In their editorial (6), Dr. Andrew Miller from Emory University and Dr. Elisabeth Binder from the Max Planck Institute of Psychiatry more deeply discuss mechanisms underlying the linkage between autoimmune disorders and stress-related psychopathology and point to the future possibility of using drugs targeted at autoimmune processes to treat subsets of patients with stress-related psychiatric disorders.

Kim et al. (7) present data from their studies in mice that are aimed at developing a better understanding of the role of the anterior insular cortex in mediating social cognition processes. This is relevant because different forms of altered social functioning and cognition have been implicated across psychiatric illnesses, as have alterations in anterior insula function. Here, the authors use a mouse model to uncover the molecular mechanisms within the anterior insula that are important in these processes. First, using lesions that selectively kill neurons, the authors demonstrated involvement of anterior insula neurons in behaviors associated with recognizing and interacting with a novel conspecific. Next, using various methods, including 1) infusing retinoic acid into the anterior insula, 2) a viral vector method to knock down the expression of a retinoic acid-degrading enzyme (cytochrome P450 26B1), and 3) cytochrome P450 26B1 conditional knockout mice, the authors show involvement of the retinoic acid pathway in mediating social novelty recognition. This finding is of interest since the retinoic acid signaling pathway is critical for fetal neural development, is involved in the regulation of various genes, and later in life is involved in synaptic plasticity (8). Consistent with the role of the retinoic acid pathway in neuroplasticity, the researchers found that the P450 26B1 knockout mice had alterations in dendritic spine density and function in layer 5 anterior insula pyramidal neurons. In addition to the retinoic acid pathway, the authors also investigated the involvement of oxytocin in the anterior insula in mediating social novelty recognition. The rationale for studying oxytocin is based on its role in attachment bond formation and in modulating social functioning as well as its hypothesized role in disorders such as ASD. The findings from these studies demonstrated that oxytocin promotes social novelty recognition through indirect pathways that involve the modulation of dorsal raphe serotonergic neurons that project to the anterior insula. Taken together, these findings implicate anterior insula cortical layer 5 pyramidal neurons as being important for social recognition processes in mice. The findings further suggest that molecular mechanisms involving interactions among retinoic acid, serotonin, and oxytocin signaling modulate the function of these neurons as they relate to normal and altered social cognition. In his editorial, Dr. John Christianson from Boston College (9) further explains the methods used in this paper and the interpretation of the findings in relation the value and limitations of their translatability to humans.

This issue of the Journal presents research that uses sophisticated scientific methods, some using behavioral neuroscience approaches, to address questions that are of considerable clinical importance. The methods highlighted in these studies include genetic and familial analyses, molecular in vivo imaging, and brain-based molecular manipulations in an animal model. The main findings include: 1) the possibility that anterior cingulate cortex mitochondrial dysfunction is relevant to ASD; 2) that polygenic risk scores for neuroticism and resilience are independent of family history in predicting the risk to develop mood and psychotic disorders; 3) that autoimmune and stress-related psychiatric disorders have some shared genetic underpinnings, and 4) the importance of retinoic acid, oxytocin, and serotonin pathways in modulating anterior insular cortex function as it relates to adaptive and maladaptive processes relevant to social cognition.

In addition, these articles serve as reminder of the importance of combining clinical studies with basic science research. This approach is critical in our quest to achieve a better understanding of the etiology and pathophysiology of psychiatric illnesses. Although the process of scientific discovery can be slow, and some are discouraged by the lack of more rapidly available and clinically applicable findings, it is critical that we enthusiastically support the scientific efforts of psychiatric and neuroscience researchers. Significant diagnostic and treatment advances that will impact our patients and their families will only be made by investing in basic and clinical research and by encouraging investigators to use translational approaches to work collaboratively across basic and clinical levels.