Depression is one of the leading causes of disability worldwide, with many patients inadequately treated, and at its worst results in suicide. Thus, new therapeutic strategies are critically needed. Such strategies require a holistic understanding of the precise neuronal subtypes and molecular mechanisms underlying depression. Imaging and genetic studies have identified key neurobiological markers in depressed patients. However, information relating maladaptive neuronal populations in depression with the genetics of depression is lacking. We can overcome this limitation by employing a multidisciplinary approach to investigate a novel risk gene for major depressive disorder (MDD), the neuronal amino acid transporter Slc6a15, and endogenous opioid signaling in a nucleus accumbens microcircuit, which is known to mediate negative emotional states. Our studies employ a multidisciplinary approach including cell subtype and circuit selective molecular profiling, cell subtype genetic targeting, and optogenetics to uncover novel molecular mechanisms in this nucleus accumbens microcircuit in depression. We have the ability to profile Slc6a15 levels in selective neuron populations in preclinical models of depression. In parallel we have developed novel genetic tools to manipulate Slc6a15 levels in selective neuronal populations and assess the impact of Slc6a15 levels in depression related behaviors in rodents. Using these tools we will assess the effects of Slc6a15 on endogenous opioid signaling and study how altering endogenous opioid signaling, within this nucleus accumbens microcircuit, impacts depression related behaviors. Findings from these proposed studies could uncover multiple avenues of therapeutic targeting that can greatly impact the lives of individuals suffering from this chronic disease.

Public Health Relevance

We propose to study the neuro-circuit and molecular mechanisms underlying depression. We will genetically target a depression risk gene in a nucleus accumbens microcircuit and investigate endogenous opioid signaling in this microcircuit in preclinical models of depression. Our proposed studies could uncover novel therapeutic targets for antidepressant treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH106500-03
Application #
9220649
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2015-04-15
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Terrillion, C E; Dao, D T; Cachope, R et al. (2017) Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. Genes Brain Behav 16:495-505
Francis, T Chase; Lobo, Mary Kay (2017) Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression. Biol Psychiatry 81:645-653
Chandra, Ramesh; Lobo, Mary Kay (2017) Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction. Front Behav Neurosci 11:112
Francis, T C; Chandra, R; Gaynor, A et al. (2017) Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry 22:1512-1519
Castro, Alberto; Li, Ying; Raver, Charles et al. (2017) Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons. Pain 158:1366-1372
Terrillion, Chantelle E; Francis, T Chase; Puche, Adam C et al. (2017) Decreased Nucleus Accumbens Expression of Psychiatric Disorder Risk Gene Cacna1c Promotes Susceptibility to Social Stress. Int J Neuropsychopharmacol 20:428-433
Chandra, Ramesh; Francis, T Chase; Nam, Hyungwoo et al. (2017) Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility. J Neurosci 37:6527-6538