ETI

Pilot Project

Christoph Buettner
Christoph Buettner, MD, PhD
Assistant Professor Medicine, Endocrinology, Diabetes and Bone Disease
Assistant Professor Neuroscience
Mount Sinai School of Medicine

Role of insulin signaling in regulating thalamic MDN gene expression

Schizophrenia is a non-Mendelian, genetically heterogeneous disorder which is defined clinically by symptom clusters impacting a person's perception, cognition and behavior. A promising task ahead in schizophrenia research is to link recent genomic and genetic data and that of neuroimaging studies of living subjects with the underlying neuropathology impacting various brain regions. As such, the role of insulin signaling, glucose hypometabolism and the possibility of neuronal insulin resistance in the brain of persons suffering schizophrenia has become a very important area of study. Dysregulation of prefrontal cortical activity involved in working memory and executive functioning, which are dysfunctional in persons suffering schizophrenia, has been reported in both animals and humans. Various postmortem and in vivo anatomical and functional studies have identified the mediodorsal nucleus (MDN) as having less relative glucose utilization likely representing less relative neuronal activation. Owing to reciprocal connectivity, the thalamic nuclei and their cortical fields act as functional units. We have accumulatively collected a highly enriched neuronal population from the parvocellular subregion of the MDN (MDNp) of postmortem samples and have performed microarray analysis identifying gene expression changes in IGF-1/mTOR and AKt signaling pathways in SZ. In addition, there is mounting evidence for dysregulation of brain insulin receptors and insulin-dependent Akt signaling. For instance, pharmacologic stimulation of muscarinic and insulin/IGF1 receptors reverses the gene expression changes in specific subsets of genes that have been shown to be dysregulated in SZ, further highlighting the importance of insulin signaling. Thus, converging evidence from various lines of study implicate insulin receptor deficits in dorsolateral prefrontal cortex (DLPFC), reduced utilization of glucose by the MDN and PFC, as well as AKT1 as a risk gene for SZ. However, it is unclear if these genes identified are truly under the transcriptional control of insulin signaling in the thalamus and if a similar dysregulation in gene expression can be induced by selective insulin resistance in the MDNp. The Buettner lab has studied the role of insulin signaling in the mediobasal hypothalamus (MBH), a brain region that is important in metabolic control. From these studies it is clear that insulin does signal in neurons and it also established the methodology used in the experimental design of this proposal. Since the MBH is an insulin responsive brain region we will use the MBH as a positive control for brain insulin studies for our proposed MDN microarray studies in rat brain. Thus, we propose to study the role of insulin signaling in the transcriptional regulation of these same target genes that we identified in SZ postmortem samples by employing a series of well-controlled in vivo clamp studies in rat inducing either systemic versus MDN selective insulin signaling. If we can demonstrate that insulin signaling indeed regulates MDNp transcription of these genes then we could a) determine in vivo insulin resistance of the MDNp and other brain region using functional MRI during hyperinsulinemic clamps in humans, and b) test if intranasal, i.e. brain specific delivery of insulin improves schizophrenia in humans.