Kalivas Laboratory

Our lab conducts experiments intended to reveal the neurobiological underpinnings of substance use disorders and anxiety disorders such as PTSD. In doing so, we endeavor to identify molecular targets and provide biological rationales for designing pharmacotherapeutic treatments. Thus, our work spans animal models of addiction at the level of molecular physiology and morphology to clinical collaborations conducting brain stimulation and clinical trials in human subjects. We focus on the long-lasting changes in brain function produced by drug use and a single strong stress that create the enduring vulnerability to environmental cues producing relapse to drug use or stress-associated behaviors. In the course of the last 15-20 years of research we have come to a conclusion that impairments in how the prefrontal cortex regulates motivational circuitry in the striatum are a critical drug- and stress-induced pathology. Accordingly, much of our work focuses on how addictive drugs and stress regulate glutamatergic neurotransmission and synaptic plasticity in the nucleus accumbens (the brain portal whereby prefrontal cortex initiates behavioral change and adaptation), and on accumbens projections to the ventral pallidum and its downstream targets. Importantly, while we quantify classic synaptic physiology and morphology, we have come to the conclusion that critical adaptions conferring vulnerability to relapse and the intensity of the drug seeking or stress responding are to be found in perisynaptic astroglia and extracellular matrix, that together with the pre- and postsynapse form a homeostatic compartment referred to as the tetrapartite synapse.

Major Research Projects:

Project 1 – Understanding addiction through tetrapartite synapses

This project expands on our discovery that relapse in the reinstatement model requires the rapid induction of transient synaptic potentiation (t-SP) in accumbens spiny cells. When an animal experiences a drug-conditioned cue t-SP occurs and this is correlated with the intensity of the behavioral response. Transient-SP occurs regardless of whether the animal was trained to self-administer cocaine, heroin or nicotine. Following up on this finding has resulted in establishing the model shown below, whereby down-regulated glutamate transport in astroglia and a retraction of astroglial processes adjacent to synapses causes synaptic glutamate spillover to stimulate nNOS interneurons, which activates matrix metalloproteases (MMPs). The activated MMPs create ligands for integrin receptors that signal postsynaptic insertion of AMPA receptors and dendritic spine enlargement (e.g. how we measure t-SP). In addition to clarifying details of this model, in future studies we are examining whether we can manipulate this microcircuit and thereby turn a biological reinforcer into a drug-like compulsive reinforcer and vice versa.

Project 2 – Understanding subcircuits that regulate addiction

Another project is to examine circuitry distal to the nucleus accumbens mediating relapse to addictive drugs. For this project we have characterized the cell subtypes in the ventral pallidum and the subtypes of accumbens cells that provide afferents. Additionally, we find enduring drug-induced synaptic plasticity selectively in some ventral pallidal subcircuitry and only in certain subtypes of nucleus accumbens neurons. To make these discoveries we use transgenic rodents coupled with viral transgenes to study the physiology, morphology and function of each subcircuit. This includes measurements of calcium transients using miniscopes attached to implanted lenses where we specifically study how D1- and D2-medium spiny neurons have different patterns of activity in response to cocaine use and cued seeking. We compare this activity between sucrose and cocaine trained rats in order to find a pattern unique to drug reward versus natural reward. Finally, we are examining how prefrontal cortical inputs regulates calcium activity in D1- and D2-expressing neurons between cocaine and sucrose reward and seeking.

Project 3 – Understanding how PTSD correlates with substance abuse

We have a model of PTSD comorbidity with substance use disorder, with a focus on heroin and cannabis abuse. Acute restraint stress leads to long term plasticity in cortico-accumbens projections and tetrapartite accumbens synaptic plasticity that strongly resembles the tetrapartite plasticity produced by drug self-administration (as outlined in Project 1). Moreover, associating stress with a conditioning odor causes odor induces tetrapartite synaptic plasticity and alters cue-induced seeking of cocaine, heroin and cannabis.

Project 4 – Understanding the neurobiological differences between heroin vulnerable and resilient rats.

We use a non-linear clustering approach of 7 heroin related behaviors to segregate outbred rats into heroin vulnerable and resilient populations. We then examine differences in cue-induced c-fos expression and starting to employ a brain clearing protocol to identify brain-wide circuitry differences between heroin vulnerable and resilient and sucrose trained rats. We also examine patterns of dendritic and astroglial morphology in the different subpopulations.

Team

Peter Kalivas, Ph.D.
Distinguished Professor
Peter received his Ph.D. from the University of Washington in 1980 with Akira Horita and completed postdoctoral training at the University of North Carolina with Art Prange in 1982. He moved to Charleston from the West Coast and began a position as Professor and Founding Chair of Neuroscience in 1998. He stepped down from department chair in 2019 and is currently a Distinguished University Professor of Neuroscience. Outside the lab, Peter likes to travel to off-beat places.

Brittany Kuhn, Ph.D.
Research Assistant Professor
Brittany received her B.S. in Biology from Virginia Tech and her Ph.D. in Neuroscience from the University of Michigan. During her graduate work with Dr. Shelly Flagel, she studied the role of the paraventricular nucleus of the thalamus and its associated circuitry in mediating individual variation in relapse propensity. Brittany joined the lab in February of 2019 and is focusing on two main projects: how individual variation in addiction-related behaviors contributes to vulnerability versus resiliency to opioid dependence; and using intersectional viral and cell-type specific approaches to elucidate the role of efferent projections from the ventral pallidum on behavior during extinction training and reinstatement of cocaine-seeking behavior. Outside of the lab, Brittany loves running, anything soccer, traveling and exploring new places in Charleston.

Ritchy Hodebourg, Ph.D.
Post Doctoral Fellow
Ritchy received his M.Sc. in Neurosciences from University of Poitiers, France in 2013, and his Ph.D. in Neuropharmacology from University of Montreal, Canada in 2019. During his M.Sc. he investigated the influence of N-acetylcysteine on heroin seeking behavior under the supervision of Dr. David Belin. He then moved to Canada as a Ph.D. student. The main goal of his thesis, supervised by Dr. Pierre-Paul Rompré, was to determine the effect of N-acetylcysteine on the motivation to self-administer cocaine in rat. Ritchy joined the Kalivas lab in June, 2019 and is studying how pre-exposure to single traumatic event impacts cannabis self-administration and how cannabis use affects responsivity to a stress-conditioned stimulus in rats. Outside the lab, as a former top athlete in fencing, Ritchy enjoys playing sports and listening to music.

Anze Testen, Ph.D.
Post Doctoral Fellow
Anze received his Bachelor’s and Master’s degrees from the University of Ljubljana (Slovenia) in Biology and Molecular Biology, respectively. He then moved to University of North Carolina at Chapel Hill where he studied structural plasticity of astrocytes and microglia following drug self-administration and withdrawal under the mentorship of Dr. Kathryn Reissner. After graduating in 2021 he joined Kalivas lab in 2022 to explore the interplay between different neuronal subpopulations as well as glia-neuron interactions in Nucleus Accumbens core during reward-seeking behavior using in vivo imaging. Outside the lab Anze enjoys exploring Charleston’s beaches, breweries and eateries as well as trying desperately to find a suitable mound of dirt that would enable him to continue mountain biking in the lowcountry.

Shoele Jamali, Ph.D.
Post Doctoral Fellow
Shoele received her Ph.D. in Neuroscience from Shahid Beheshti University of Medical Sciences, Iran. Her thesis investigated the neural activity of the hippocampus and nucleus accumbens in natural and morphine induced reward using in vivo electrophysiological recordings under the supervision of Dr. Haghparast. Following graduation, she gained experience in circuit neuroscience and slice electrophysiology at Christian Lüscher's Lab in Geneva, as a visiting scientist. Shoele joined the Kalivas lab in June 2023. Her current research focuses on comparing the effects of drug and natural cue-seeking on brain circuitry within the same animal using a dual self-administration model adapted for in vivo single-cell calcium imaging in the NAc. Outside the lab, Shoele enjoys playing sports, running, and watching movies.

Brice Ayissi, Ph.D.
Visiting Scientist
Brice received his bachelor’s and master’s degrees from the University of Yaoundé 1 (Cameroon) in Biochemistry. He then moved to the University of Tuebingen (Germany) where he studied the neuroprotective effects of chemical lead compounds using transgenic mice models of Alzheimer’s disease under the supervision of Prof Hermann Schluesenner and Paul Moundipa. After graduating in 2015, he completed postdoctoral training at the University of South Carolina and at the Medical College of Wisconsin in 2019. In 2020, Brice went back to Cameroon where he works as senior lecturer of neuroscience and molecular biology with main research area focusing on fighting drug addiction among the youth. Early this year, he joined Dr Kalivas lab as a visiting NIDA research scholar (INVEST Award) to explore the cell and circuit specific pathways regulating heroin seeking and refraining behavior. Outside the lab, Brice enjoys playing soccer and loves to hit the gym.

Samson Sahile Salile, Ph.D.
Visiting Scientist
Samson received his bachelor’s degree at Mekelle University and his Ph.D. in Medical Pharmacology and a D.V.M from Addis Ababa University in Ethiopia. He is currently a Lecturer at in the School of Medicine at Arba Minch University, Ethiopia. He has come to the Kalivas Lab on a fellowship from the International Neurochemistry Society to learn techniques for understanding the brain circuitry underpinning substance use disorders.

Eric Dereschewitz, B.A.
Lab Manager
Eric received his Bachelor’s degree in Biology from the College of Charleston, in Charleston, S.C. in 2016. Eric first joined the Kalivas lab in January 2017 as a technician and transitioned over as Lab Manager in January 2018 and manages the day-to-day activities such as maintaining and updating animal protocols, and animal breeding colonies and ordering for the lab. Outside of the lab, Eric enjoys cycling, discovering new restaurants and engaging in the downtown Charleston social life.

Stephen Walterhouse, M.Sc.
Research Specialist
Stephen received his Bachelor’s degree in Biology from the University of South Carolina and his M.Sc. in Biology from Kansas State University. In his graduate studies Stephen investigated trans-lesion synthesis pathway protein expression and stability variations between primary keratinocytes and cervical cancer cell lines, as well as due to growth factor deprivation. Stephen joined the lab in March, 2021 managing the microscopy and analysis portions of various projects. Outside of the lab, Stephen enjoys outdoor activities (especially climbing), going to extreme metal concerts, and having an engaging social life.

Lillian Duncan, B.A.
Research Technician

Kalivas Laboratory Recent Publications (2022-present)

Kruyer, A D. Dixon, A. Angelis, D Amato and PW Kailvas. 2022. Astrocytes in the ventral pallidum extinguish heroin seeking through GAT-3 upregulation and morphological plasticity in D1-MSN terminals. Mol Psychiatry, 27: 855-864. PMC9054673

Nall, RW, RM Chalhoub and PW Kalivas. 2022. Drug versus Non-Drug Behaviors: A Dual-Reward Model of Sex Differences and Neurobiological Mechanisms in Rats. J Exp. Analysis Behav., 117: 457-471.

Hodebourg, R, M Meyerinck, A Crow, C Reichel, PW Kalivas* and C Garcia-Keller*. 2022. Cannabis use changes conditioned stress responses. Neuropsychopharmacology, 47: 1037-1045. PMC8938410

Hodebourg, R, PW Kalivas* and A Kruyer. 2022. Extrasynaptic therapeutic targets in substance use and stress disorders. Tr Pharm Sci (TiPS), 43: 56-68. PMC8688303

Bradlow, RCJ, M Berk, PW Kalivas, SE Back and RA Kanaan. 2022. The potential of N-acetyl-L-cysteine (NAC) in treating psychiatric disorders. CNS Drugs, 36: 451-482. PMC9095537

Kruyer, A, A Angelis, C Garcia-Keller, H Li and PW Kalivas. 2022. Plasticity in astrocyte subpopulations regulates heroin relapse. Science Advances, 8, https://www.science.org/doi/10.1126/sciadv.abo7044 PMC9365285

Kruyer, A*, PW Kalivas* and MD Scofield*. 2023. Astrocyte regulation of synaptic signaling in psychiatric disorders. Neuropsychopharm Rev, 48: 21-36. PMC9700696

Kuhn, BN, N Cannella, AD Crow, AT Roberts, V Lunerti, C Allen, RW Nall, G Hardiman, LC Solberg-Woods, D Chung, R Ciccocioppo and PW Kalivas. 2023. Novelty-induced locomotor behavior predicts heroin addiction vulnerability only in male rats. Psychopharmacology, 239: 3605-3620. PMC9632364

Garcia-Keller, C, K Seidling, LN Beloate, V Chioma, S Spencer, PW Kalivas and D Neuhofer. 2023. Delta-9-tetrahydrocannabinol self-administration induces cell-type specific adaptations in the nucleus accumbens core. Addict Biol,28(8):e13286 PMC10924663

Neuhofer, D and PW Kalivas. 2023. Differential GABAA transmission and neuropeptidergic modulation allow gating of GABAergic and glutamatergic cells in the ventral pallidum. eNeuroscience, 10(7):ENEURO.0404-22.2023 PMC10348443

Kanaan, RA, G Oliver ……….PW Kalivas, M Berk. 2023. A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-acetylcysteine for treatment-resistant PTSD. Psychiat Res 327:115398. PMID: 37540942

Fredriksson, I, PA Melas, PW Kalivas, N Jayaram-Lindstrom and P Steensland. 2023. N-acetylcysteine improves impulse control and attenuates relapse-like alcohol intake in long-term drinking rats. Behavioral Brain Res, 5:436:114089 PMID: 36063970

Kalivas, PW, SL Gourley and MP Paulus. 2024. Intrusive thinking: Circuit and synaptic mechanisms of a transdiagnostic psychiatric symptom. Neurosci Biobehav Rev, in press, PMC10249786.

Mozafari, R, S Karimi-Haghighi, M Fattahi, PW Kalivas and A Haghparast 2023. A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Prog Neuro Biol Psychiat, 8: 124:110735. PMID: 36813105

Kuhn, BN, N Cannella……..and PW Kalivas. 2024. Multi-symptomatic modeling of heroin use disorder reveals distinct behavioral profiles and neuronal correlates of heroin vulnerability and resiliency in rats. Am J Psychiatry, in press

Cannella, N, S Tambalo………PW Kalivas…….R Ciccocioppo. 2024. Long-access heroin self-administration induces region specific grey matter volume reduction and microglial reaction in rat. Brain Behav Immunity, in press.

Mozafari, R, F Khodaholi, N Kaveh, ME Zibali, PW Kalivas and A Haghparast 2024. Blockade of mGluR5 in nucleus accumbens modulates calcium sensor proteins, facilitates extinction and attenuates reinstated morphine place preference in rats. Prog Neuro Biol Psychiat, in press.

Lewandowski, SI, R Hodebourg, SK Wood, JS Carter, KH Neson, PW Kalivas and CM Reichel. 2023. Matrix metalloproteinase activity during methamphetamine cued relapse. Addict Biol, 28:e13279. PMC10506177

Greenberg, JM, AD Winters, B Zagorac, DJ Dratch, DM Fancescutti, N Cannella, R ciccocioppo, LC Solberg-Woods, J Mackle, GT Hardiman, BN Kuhn, PW Kalivas, DM Kuhn and M Angoa-Perez. 2024. Long access heroin self-administration significantly alters gut microbiome composition and structure. Front Psychiatry, in press.

Aiyetigbo, M, A Korte, E Anderson, R Chalhoub, PW Kalivas, F Luo and N Li. 2024. Unsupervised microscopy video denoising. CVPR Workshop 2024, in press.

Full list of publications https://www.ncbi.nlm.nih.gov/pubmed/?term=kalivas