Opiate abuse potentiates the neuropathogenesis of HIV by synergistically increasing dendritic pathology (varicosity formation, beading, fragmentation, pruning), while promoting additive dendritic spine losses (plasticity). Behavioral deficits in spatial and non-spatial memory tasks are accompanied by synaptic losses and dendritic pathology preceding neuron death, suggesting that neuronal injury and reduced synaptic connectivity underlie the ability of opioids to aggravate HIV-associated neurological disorders (HAND). We have found that phenotypically distinct subpopulations of hippocampal CA1 interneurons appear to be highly sensitive to Tat opiates, and disruptions to these interneuron subpopulations may contribute, in part, to pyramidal cell dysfunction/injury. These findings represent a fundamental shift in our understanding of opioid drug action and propel the grant in novel directions. We hypothesize that opiates and HIV-induced hippocampal behavioral dysfunction is caused by disruptions to synaptic function and organization in vulnerable neuronal subpopulations that disrupt specific neural networks within the hippocampus.
Aim 1 will characterize the neurophysiologic events underlying opioid and HIV-dependent neuronal dysfunction and injury in hippocampal CA1 pyramidal cells in whole-cell, patch-clamp recordings of CA1 pyramidal cells. Alterations in long-term potentiation and depression will be explored, as will deficits in subthreshold postsynaptic potentials in response to opiates and Tat. During patch-clamp recordings, neurons will be biocytin-filled and subsequently analyzed via 3D-reconstruction for dendritic pathology and spine density.
Aim 2 will determine how vulnerable subsets of MOR-expressing CA1 interneurons exacerbate opiate and HIV-1-induced hippocampal dysfunction, neuronal injury, and disrupt network function. Tat tg mice will be crossed with MORfloxed;VGAT-Cre mice, which lack MOR+ CA1 interneurons. We will also determine how Tat and opiates affect synaptic processing and network function in CA1 by examining the integration of synaptic inputs by imaging genetically encoded-voltage indicators (GEVIs) selectively expressed in CA1 pyramidal neurons.
Aim 3 will identify the neurophysiologic mechanisms underlying opiate and infectious HIV-1/HIV protein-induced neuronal dysfunction and injury in human hippocampal neurons. Opiate and Tat-induced neurophysiological and structural deficits will be correlated with deficits seen in Tat mice assessed in Aims 1 and 2. Our long-term goal is to define the mechanisms by which opiate drug abuse exacerbates neurodegenerative and functional defects, and to identify key underlying events that could be targeted therapeutically.

Public Health Relevance

We recently discovered that hippocampal interneurons and their associated glia highly vulnerable to opiate abuse and HIV co-exposure. The hippocampus is responsible for spatial and non-spatial learning and memory, and this is severely disrupted by opiate drug abuse and HIV comorbidity. Our long-term goal is to identify how these neuronal networks and interrelated glia that are damaged by opiate abuse and HIV, and ultimately determine how structural and functional deficits in hippocampal neural circuitry might be rescued therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018633-12
Application #
9413997
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Lin, Yu
Project Start
2005-09-30
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Schier, Christina J; Marks, William D; Paris, Jason J et al. (2017) Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice. J Neurosci 37:5758-5769
Gonek, Maciej; McLane, Virginia D; Stevens, David L et al. (2017) CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward. Brain Behav Immun :
Marks, William D; Paris, Jason J; Schier, Christina J et al. (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neurovirol 22:747-762
Fitting, Sylvia; Stevens, David L; Khan, Fayez A et al. (2016) Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice. J Pharmacol Exp Ther 356:96-105
Guedia, Joy; Brun, Paola; Bhave, Sukhada et al. (2016) HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system. Sci Rep 6:31203
Hahn, Yun K; Paris, Jason J; Lichtman, Aron H et al. (2016) Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and ?-arrestin 2 activity in the forebrain. Neurobiol Dis 92:124-36
Hahn, Yun Kyung; Podhaizer, Elizabeth M; Farris, Sean P et al. (2015) Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct 220:605-23
Fitting, S; Ngwainmbi, J; Kang, M et al. (2015) Sensitization of enteric neurons to morphine by HIV-1 Tat protein. Neurogastroenterol Motil 27:468-80
Sorrell, Mary E; Hauser, Kurt F (2014) Ligand-gated purinergic receptors regulate HIV-1 Tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures. J Neuroimmune Pharmacol 9:233-44
El-Hage, Nazira; Rodriguez, Myosotys; Podhaizer, Elizabeth M et al. (2014) Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine. AIDS 28:1409-19

Showing the most recent 10 out of 30 publications