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Principal Investigator: Sylvia Fitting
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $194,375
Funding agency: National Institute on Drug Abuse
Project Summary
In the context of human immunodeficiency virus (HIV) infection, cannabis use is an important topic and is the
most commonly used drug among people living with HIV (PWH), despite the success of combined antiretroviral
therapy (cART). Cannabis use is known to alleviate common symptoms and complications in PWH on cART,
including chronic pain, nausea, and anxiety/depression, but contradicting results have been reported for
cannabis use on cognitive performance. As cART does not cross the blood brain barrier the prevalence of mild
to moderate forms of cognitive impairments, known as HIV-1-associated neurocognitive disorders (HAND),
remain high (50%). Brain regions that are specifically vulnerable to HIV include the frontostriatal system,
involving deficits in learning, memory and reward-related behaviors. HIV-1 proteins released by HIV-1 infected
cells, including the transactivator of transcription (Tat) protein, are known to play a major role in the underlying
HAND neuropathology, including lasting changes in neuronal excitability, inflammatory processes, and synaptic
communication. Nevertheless, it is not clear how neuronal activity is altered by HIV Tat during learning while an
animal is performing a behavioral task, i.e in the context of reward. With the establishment of in vivo calcium
imaging, it has been shown that dorsomedial prefrontal cortex neurons that project to the nucleus accumbens
(PFC-NAc) increase their neuronal activity after successful appetitive discrimination learning. The goal of the
proposed study is to determine cannabis-induced changes on neuronal activity in a neuroHIV mouse model
during performance of a behavioral reward-related learning task and its relation to the endocannabinoid (eCB)
system. To achieve this goal, we will make use of a well-established mouse model of neuroHIV and propose two
aims. Aim 1 will determine how CBD:THC ratios alter prefrontal neuronal activity in HIV Tat transgenic male and
female mice performing a reward-related learning task. Animals will undergo viral injections to visualize in vivo
calcium activity in PFC-NAc neurons and drug administration starts with behavioral assessment. Head-fixed
mice will be trained to perform a Pavlovian conditioning task, that presents reward-predictive cues, and tests
animal’s ability to learn to discriminate between a conditioned stimulus that predicts sucrose reward (CS+) but
not the other (CS-). Neuronal activity will be recorded throughout training and compared before and after
learning. Aim 2 will determine the effect of different CBD:THC ratios (1:15, 1:1, 15:1) on the eCB system and
pathology in relation to appetitive discrimination learning in HIV Tat transgenic mice. Immunohistochemistry will
be used to assess cell-specific localization of cannabinoid-like receptors (CB1R, CB2R, GPR55) and catabolic
enzymes (FAAH, MAGL) on neurons, astrocytes, and microglia in the dorsomedial PFC and NAc; (non-)eCB
ligands (e.g. AEA, 2-AG, AA, OEA, PEA) will be quantified using ultraperformance liquid chromatography-
tandem mass spectrometry. This work will advance the understanding about how alterations in neuronal activity,
inflammation, and cannabis-induced changes in the eCB system contribute to HIV-related symptoms.
Terms: <2-AG><2-arachidonoyl-glycerol><2-arachidonoyl-sn-glycerol><2-arachidonoylglycerol><2-arachidonyl-glycerol><2-arachidonylglycerol><21+ years old><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adult><Adult Human><Age Months><Animal Testing><Animals><Anxiety><Appetite><Association Learning><Associative Learning><Astrocytes><Astrocytus><Astroglia><Behavior><Behavior assessment><Behavioral><Brain><Brain Nervous System><Brain region><CB1><CB1 Receptor><CB1R><CB2><CB2 Receptor><CB2R><CNR1 gene><CNR2><CNR2 gene><Calcium><Cannabinoid Receptor CB1><Cannabinoid Receptor CB2><Cannabinoids><Cannabis><Cell Body><Cells><Chronic><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communication><Conditioned Stimulus><Cues><Desire for food><Discrimination Learning><Disease><Disorder><Disturbance in cognition><Dose><Drug usage><Drugs><Encephalon><Endocannabinoids><Endogenous Cannabinoids><Enzyme Gene><Enzymes><Experimental Designs><Exposure to><Female><GPR55><GPR55 receptor><Gene Transcription><Genetic Transcription><Genotype><Goals><HIV><HIV 1 associated neurocognitive disorder><HIV associated neurocognitive deficit><HIV associated neurocognitive impairment><HIV associated neurological disease><HIV associated neurological disorder><HIV induced neurocognitive deficit><HIV induced neurocognitive impairment><HIV neurocognitive impairment><HIV-1><HIV-1 associated neurocognitive deficit><HIV-1 associated neurocognitive disorder><HIV-1 associated neurocognitive impairment><HIV-I><HIV-associated neurocognitive disorder><HIV1><Head><Hortega cell><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impaired cognition><In vivo two-photon calcium imaging><Induced Neurons><Inflammation><Inflammatory><Injections><LAV-HTLV-III><Learning><Ligands><Liquid Chromatography><Lymphadenopathy-Associated Virus><Medication><Memory><Mental Depression><Mice><Mice Mammals><Microglia><Modern Man><Mouse Protein><Murine><Mus><Nausea><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocognition><Neurocognitive Impairment in HIV><Neurocognitive Impairment in HIV-1><Neurocyte><Neuron Degeneration><Neuronal Dysfunction><Neurons><Nucleus Accumbens><Outcome><Pathology><Pavlovian conditioning><Performance><Persons><Pharmaceutical Preparations><Pisum sativum><Play><Prefrontal Cortex><Prevalence><Process><Proteins><RNA Expression><Receptor Protein><Recovery><Reporting><Rewards><Role><Saccharose><Sucrose><Symptoms><Synapses><Synaptic><System><THC co-use><THC exposure><THC use><Tetrahydrocannabinol co-use><Tetrahydrocannabinol use><Therapeutic><Training><Trans-Acting Factors><Trans-Activators><Transactivators><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Regulation><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Transgenic Organisms><Viral><Viral Diseases><Virus Diseases><Virus-HIV><Visualization><Work><adulthood><antiretroviral therapy><antiretroviral treatment><associative conditioning><astrocytic glia><behavior test><behavioral assessment><behavioral test><cannabinoid receptor 1><cannabinoid receptor 2><cannabinoid receptor type 1><cannabinoid receptor type 2><cannabinoid therapeutics><cannabinoid therapy><cannabinoid treatment><cannabinoid type 1><cannabinoid-based therapeutic><cannabinoid-based therapy><cannabinoid-based treatment><cannabis use><chronic pain><classical conditioning><cognitive dysfunction><cognitive function><cognitive loss><cognitive performance><cohort><common symptom><depression><drug use><drug/agent><eCB system><endocannabinoid system><endogenous cannabinoid system><excitotoxic><excitotoxicity><gitter cell><humanized mice><humanized mouse><iNeuron><in vivo><in vivo calcium imaging><innovate><innovation><innovative><male><marijuana use><mesoglia><microglial cell><microgliocyte><mouse model><murine model><neural degeneration><neural dysfunction><neural inflammation><neuro-AIDS><neuro-HIV><neuroAIDS><neuroHIV><neurocognitive disorder><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuronal excitability><neuropathologic><neuropathological><neuropathology><novel><pea><perivascular glial cell><pre-clinical study><preclinical study><receptor><response><social role><success><synapse><tandem mass spectrometry><tetrahydrocannabinol exposure><transcription co-activator><transcriptional co-activator><transgenic><viral infection><virus infection><virus-induced disease>