2018 Breakthrough Award

Identifying the molecular and cellular substrates of OCD using human post-mortem brain

Susanne Ahmari, MD, PhD

University of Pittsburgh (Pittsburgh, PA)

Award Amount: $500,000

Brain imaging studies in OCD patients have consistently shown abnormal activity in regions involved in decision-making (orbitofrontal cortex [OFC]) and transmission of sensory information (thalamus). However, we have no knowledge regarding the changes in these regions happening on a molecular level that contribute to abnormal function in people with OCD.

To fill this gap, Dr. Ahmari’s prior work focused on targeted gene expression studies that showed down-regulation of genes in the OFC associated with excitatory synaptic transmission – essentially leading to less efficient decision-making. However, what is causing these concerted changes? One cohesive explanation is that an OFC input structure, such as the thalamus, acts as the source of molecular changes, and that the OFC compensates accordingly when it receives this input from the thalamus. Dr. Ahmari and her team will investigate this further by using RNA-sequencing in post-mortem OFC and thalamus brain tissue from OCD patients and a matched post-mortem control group. The goal is to uncover the biological networks most affected in OCD patients, through techniques such as differential gene expression, gene co-expression, and pathway analysis. Together, these experiments will lead to identifying key molecular changes underlying the pathology of OCD, with the ultimate goal of finding novel targets and developing more effective treatments.