Speaker:

Dr Susannah Tye

Director, Translational Neuroscience Laboratory, Mayo Clinic Depression Center, Rochester, MN, USA

Title: "Metabolic Deficits in Antidepressant Resistance are a Functional Target for Neuromodulation"

Abstract:

Background: Deficits in synaptic plasticity contribute to poor treatment outcomes in refractory psychiatric illness. Our work aims to determine the neurobiological mechanisms that functionally limit therapeutic neuroadaptations to first line antidepressant treatments in preclinical (rodent) models, together with the mechanisms of action of novel therapeutics including deep brain stimulation (DBS) and low dose ketamine.

Methods: Using a genome-wide transcriptomics approach we have identified molecular pathways contributing to antidepressant treatment resistance in rats.  Functional differences in cell signaling pathways were validated in replicate samples. Antidepressant-resistance was induced via chronic adrenocorticotropic hormone (ACTH; 100µg; i.p.; 14 days) treatment. Animals were allocated to stress-naïve or forced swim test (FST) stress conditions and euthanized 1 hr following stress exposure. The infralimbic cortex, a region critically implicated in regulating antidepressant responses, was dissected and global gene expression profiles obtained (Agilent).  Gene set enrichment analysis was performed (DAVID) following Bonferroni correction and KEGG pathways identified (Fisher exact score p<0.05).  Pivotal genes were validated in independent groups by rt-PCR and/or immunoblotting. The behavioral and neurobiological actions of infralimbic DBS (130Hz, 100uA, 90mS), ketamine (10mg/kg ip) and /or lithium (100 mg/kg ip) were subsequently determined. All groups consisted of n=8-12.

Results: Significant alterations were observed in key sensors of energy demand, cell division/growth, apoptosis, protein synthesis and glucose/glycogen regulation following stress.  Significantly less genes were differentially expressed following stress for ACTH pretreated animals relative to saline controls; suggestive of reduced capacity to respond under supplemental stress.  Markers of oxidative stress, hypoxia, endoplasmic reticulum stress, pro-inflammatory cytokines, nutrient deprivation and DNA damage were increased in the ACTH pretreated group. Mitochondria deficiency was confirmed in separate experiments and modulation of mTOR signaling in the infralimbic cortex was demonstrated to be associated with treatment response to DBS, ketamine and lithium. Behavioural outcomes were enhanced when ketamine was used in combination with DBS or lithium and correlated with increased activation of mTOR signaling.

Conclusions: Data suggest that metabolic deficits in key hypermetabolic nodes of the mesocorticolimbic network, such as the infralimbic cortex, may contribute to antidepressant resistance. Treatments with demonstrated efficacy in this model, including DBS, ketamine and lithium functionally overcome this impairment by facilitating metabolic efficiency, in part, via stimulation of mTOR signaling.  Such actions may be critical for initiating longer-term neural adaptations to enable recovery from treatment refractory psychiatric illnesses such as treatment resistant depression or post-traumatic stress disorder. Targeted neuromodulation strategies in combination with pharmacotherapies aimed at overcoming metabolic deficiencies hold great promise for these severely debilitating disorders. 

About Neuroscience Seminars

Neuroscience seminars at the QBI play a major role in the advancement of neuroscience in the Asia-Pacific region. The primary goal of these seminars is to promote excellence in neuroscience through the exchange of ideas, establishing new collaborations and augmenting partnerships already in place.

The scheduled QBI Neuroscience Seminar series are held on Wednesdays from 11am-12pm in the Level 7 Auditorium of the Queensland Brain Institute, Building 79, St Lucia Campus, The University of Queensland. Additional seminars may be held at other times as listed below.

 

Neuroscience Seminars archive 2005-2016