An Interview with Dr. Peter Kalivas by Donald McEachron
Note: Peter W. Kalivas, PhD, Medical University of South Carolina, is a keynote speaker at the IBNS Annual Meeting in Hiroshima, Japan. View a short bio on Dr. Kalivas below.
DLM - Dr. Kalivas, your work involves the neurophysiology of drug addiction and the issues surrounding relapse, does it not?
PK - yes, we are attempting to develop models that would allow for productive pharmaceutical intervention. Recovering from substance abuse is not a matter of will power, it is a matter of neurobiology.
DLM - kinds of criteria do you have for the models you are developing?
PK - there are three basic criteria that we employ: First, we want to make measurements during a drug-seeking event initiated by drug-associated stimuli. In other words, we want to examine how and why certain cues initiate drug-seeking behavior. Second, we want to quantify any adaptations in the tetrapartite physiology of the synapse, especially between prefrontal cortex and the nucleus accumbens. Third, we want to specifically examine adaptations that are shared by multiple classes of addictive drugs, but not natural rewards, such as food.
DLM - Tetrapartite synaptic physiology? I hate to admit this, but I'm a bit old school. When I got my PhD in neuroscience – in the last millennium – we are mostly concerned with presynaptic and postsynaptic cells. Of course I'm familiar with glial cell or astrocyte involvement but what's the fourth component?
PK - that is the proteins in the extracellular space, referred to as the extracellular matrix. Most neuroscientists don’t realize that the ECM is an active signaling domain that regulates synaptic function and physiology.
DLM - That certainly provides you with a number of different factors to examine
PK - It certainly does but that can be an advantage by providing multiple avenues by which effective interventions can be achieved.
DLM - And how are these studies proceeding?
PK - We have found that there seems to be a change in plasticity between pre-frontal cortex and nucleus accumbens during addiction relapse. For example, when we show an animal a drug-associated cue there is a transient LTP induced that is not seen with natural rewards.
DLM - And how is this manifested in terms of synaptic physiology?
PK - In multiple ways. For example, addictive drugs are associated with reductions in glutamate uptake, that leads to increased synaptic glutamate spillover when the prefrontal cortex inputs are activated by a drug cue. Also there is increased breakdown of the ECM by MMP-2,9 activity and transient synaptic potentiation. Notably, these are not changes seen with natural rewards, but are shared by all classes of addictive drug tested to date.
DLM - This would then lead to a variety of potential interventions, correct?
PK - Yes, the most readily accessible are is to restore GLT-1 activity at the astrocyte, and increase glutamate uptake, or the use of MMP inhibitors. However, there are other possible pathways as well. For example, excess glutamate binds to the mGluR5 receptor on an nNOS interneuron, releasing NO that, in turn, activates MMP-9 which then stimulates integrin signaling on the post-synaptic cell helping generate transient synaptic potentiation. This adds several potential inventions, such as blocking mGluR5, blocking or inhibiting nNOS and/or inhibiting integrin signaling.
DLM - There certainly are a lot of things going on with just that synaptic pathway.
PK -There are subtleties as well. N-acetylcysteine has been shown to inhibit heroin, cocaine, methamphetamine, THC and alcohol reinstatement. In a clinical study, however, it was initially reported to reduce cravings but not prevent relapse. However, urinalysis indicated that some 50% of the subjects were non-compliant. NAC has been used with OCD patients and has been reported to reduce intrusive negative thoughts, so perhaps by normalizing glutamate uptake and thereby preventing transient synaptic potentiation in cortico-striatal synapses, NAC is restoring top-down control. In fact, however, it is not really entirely clear how NAC might be working.
DLM - How so?
PK - Well, NAC has anti-oxidant properties and effects glutathione production as well. Its influence may well be on structural and enzymatic changes of cellular proteins, perhaps by increasing their biological half-lives. Of course, one protein candidate for this effect of NAC is the glutamate transporter.
DLM - So maybe we have to add another level to the tetrapartite synapse when discussion addiction.
PK - Indeed, science is always about uncovering layers. With each new discovery, there are new levels to be investigated. That is what makes it so much fun.
KALIVAS, PETER W. (1952-)
Kalivas is a neuroscientist best known for his work to elucidate the brain molecules and neurocircuitry that underlie drug addiction. This work is highlighted in over 400 publications and as editor of 6 books that focus on the cellular mechanisms and brain circuitry mediating psychiatric disorders. He has received national and international awards including a Merit Award from the National Institute of Drug Abuse, the Efron Award from the American College of Neuropsychopharmacology, the Governor’s Award for Research (South Carolina) and the ISPEN Foundation Prize in Neuroplasticity, he is an Honorary Professor of Neuroscience at Nanjing Medical University and the University of Cordoba, as well he is a Distinguished University Professor at both the Medical University of South Carolina and Washington State University. He was President of the American College of Neuropsychopharmacology in 2014. He received his Ph.D. in Pharmacology from the University of Washington in Seattle in 1980, and during a postdoctoral fellowship at the University of North Carolina in Chapel Hill (1980-82) he became oriented towards the role that brain circuitry plays in the regulating behavior. In his first faculty position at Louisiana State University in New Orleans (1982-84) and during a more extensive tenure at Washington State University (1984-98) he studied the cellular and molecular underpinnings of the brain circuits mediating addiction. This research perspective constitutes a primary contribution he continues to make to the field of neuroscience as Professor and Chair of the Department of Neuroscience at the Medical University of South Carolina in Charleston (1998-present).
Timing is Everything by Donald McEachron
In 2012, I wrote the following words the first chapter of my book, Chronobioengineering, Vol. 1:
“‘All in due time’; ‘A stitch in time saves nine’; ‘It’s only a matter of time’; ‘Time heals all wounds’; ‘Timing is everything’. Humans live in a society dominated by time and timing. The technology of time is everywhere from the cell phone in your pocket to the computer on your desk to the clock on the wall. As I stand in my kitchen, there is a clock glowing on my microwave oven, another clock displaying a slightly different time on my stove (I can never quite get those two clocks synchronized for some reason) and yet a third digital clock hanging on the wall. This third clock is wirelessly linked to the United States Atomic clock so I know at least one clock in the kitchen is accurate (it also supplies the current date, so I really know what time it is). Everywhere you turn, there is yet another reminder of what time it is - often leading to a sense of panic because there is, after all, never enough time.
Ironically, all of this technology may have the paradoxical result of decreasing the average person’s appreciation of time’s impact on biological systems. After all, even though the indicator of a clock changes with time, the mechanism does not really seem different at different times of day. If you know how to set your alarm clock at 6 pm, you do not expect to have to learn a new method of setting it if you were to try again at 6 am. Despite the fact that your laptop computer has a built-in clock, it is the same computer when you are trying to answer your e-mails at 4 am in the morning or 8 pm at night. And therein lies the problem – the alarm clock may be the same, and the computer, but you are not. Biological organisms cycle; they change over time in frequencies as short as milliseconds to times as long as years and beyond. Thus, while the technician repairing your computer can rely on dealing with the exact same mechanism no matter when he or she works on the device, a health care worker does not have the same luxury. You are different at 6 am and 6 pm – the effects of a treatment or therapy at 4 am in the morning can and does have radically different effects from that exact same treatment or therapy applied at 8 pm at night. Human beings, like almost every other life form on Earth, display daily rhythms in physiology and behavior.”
At the time, my primary focus was on the phenomenon of circadian rhythms – those endogenous biological rhythms with an inherent frequency approximating 24 hours and with capacity to synchronize (entrain) to various environmental cycles. These remain as a critical element to the overall physiology of organisms, as the data on the effects of circadian disruption can attest, but rhythms are universal throughout biological systems and may prove to be one of the most fundamental conditions of living organisms. Many of the factors studied in circadian physiology – entrainment, phase response curves, parametric effects – are basic to rhythms regardless of frequency. Recent studies on neural oscillations by Ceylan, et l., 2016; Hyafil, et al., 2015; Voloh and Womelsdorf, 2016; Watanabe and Hirono, 2016 and others support the pervasive nature of oscillations in the nervous system and underscore the need to understand rhythmicity if one is to truly understand brain function. It may also turn out that there is a kind of odd self-similarity in rhythmic structure. Everyone is familiar with the structure of the cardiac rhythm, with primary autorhythmic nodes enforcing a coherent timing on the remaining rhythmic components. Interestingly, this kind of organization appears to be repeated at the circadian level in mammals, with a master pacemaker (circadian node) in the suprachaismatic nucleus imposing a coherent rhythmic structure on a number of diverse endogenous circadian cells and tissues distributed throughout the body. Evolution being the conservative process it is, modifying successful methods to meet new ends, would it be a surprise if fundamental aspects of neural control were based upon autorhythmic nodes, such as found in the inferior olive’s 5-10 Hz subthreshold oscillations, entraining and desynchronizing local, regional and global neural networks to process and transmit information? The sheer volume of information available in an oscillation – frequency, phase, amplitude, range, pattern – makes such signals ideal for conveying complex informational content.
Brain rhythms have been around a long time. However, with advances in technology and imaging, new insights as the roles of endogenous oscillations and rhythmic networks are rapidly emerging. As we continue to learn more about the nature and function of neural oscillations, we may find that timing really is, after all, everything.
Ceylan, M.E., Dönmez, A., Ünsalver, B.A and Evrensel (2016). Neural synchronization as a hypothetical explanation of the psychoanalytic unconscious. Consciousness and Cognition 40: 34-44.
Hyafil, A., Giraud, A-L., Fontolan, L. and Gutkin, B. (2015). Neural cross-frequency coupling: Connection architectures, mechanisms, and functions. Trends in Neuroscience 38: 725-740.
Voloh, B. and Womelsdorf, T. (2016). A role of phase-resetting in coordinating large scale neural networks during attention and gola-directed behavior. Frontiers in Systems Neuroscience 10: 1-19. doi: 10.3389/fnsys.2016.00018
Watanabe, S. and Hirono, M. (2016). Phase-dependent modulation of oscillatory phase and synchrony by long-lasting depolarizing inputs in central neurons. eNeuro 3(5) e0066-16.2016 1–15
Call for Abstracts
Join the International Behavioral Neuroscience Society (IBNS) for the 26th Annual Meeting on June 26-30, 2017. Hear from best in our fields of study, establish network with scientists and researchers from all over the world, show case your work and visit Hiroshima, Japan, a vibrant city with a rich culture.
Abstracts are also now being accepted through February 21, 2017, for poster or oral presentation at the Hiroshima meeting. If you intend to present a only in poster format, you have until March 27, 2017, to submit your abstract using the 2017 Abstract Form.
Sightseeing in Hiroshima
There are two World Heritage Sites in the Hiroshima area. One is within the Hiroshima Peace Memorial. The building was designed by a Czech architect in 1915 and had been used prior to 1945 as the Hiroshima Prefectural Industrial Promotion Hall. The building was only some 160 meters from the epicenter of the atomic blast. Despite this - or perhaps because of its location, some of the building remained. In 1996, it was designated as a UNESCO World Heritage Site and remains to remind all people of the cost of war and the promise of peace.
The Hiroshima Peace Memorial Park was a busy commercial and residential area prior to 1945. After the war, Japanese architect Kenzo Tange designed the park, which was completed in 1954. A peaceful and tranquil area for quite reflection, the Park is also famous for its cherry trees, some 300 of which line the Motoyasu River, which flows along one side of the Park. River cruises are available to allow people to enjoy the cherry blossoms that bloom in the springtime. In 2006, the main building of the Hiroshima Peace Memorial Museum was designated as a National Important Cultural Property and the Peace Memorial Park was selected as a National Place of Scenic Beauty.
The second World Heritage Site is the Itsukushima Shrine located on the island of Itsukushima. The shrine encompasses almost 1400 years of Japanese history. This shrine is the only shrine in the world with a torii-gate and shrine building in the ocean itself. A torri-gate typically marks the entrance to a Shinto shrine and symbolizes moving from the profane to the sacred.
In this column, we will share the latest research, interesting scientific articles and news you can use.
Nicotine normalizes brain activity deficits that are key to schizophrenia.
Researchers at the University of Colorado, Boulder report that a constant level of nicotine helps to normalize genetically-induced brain abnormalities associated with schizophrenia. Researchers suggest that the association of schizophrenia with heavy smoking may be a form of self-medication. Read the Neuroscience News article.
Who is IBNS? by Davide Amato
With the first newsletter of 2017 we are glad to introduce a new rubric that focuses on the hobbies of our IBNS members. We are aware that for most scientists doing work in science means not only executing a profession, it also reflects the expression of a vocation where passion and curiosity are freed. Here, instead, we will be giving attention to those activities that distract us from our primary commitments and that give us a sense of healthy balance and relaxation.
According to scientists of the school of medicine at Temple University, Philadelphia, a prominent beneficial effect of hobbies is to reduce the focus from stress accumulated at work or in personal issues, boost creativity and increase positive moods. Because we also believe that hearing about other people´s hobbies may unleash psychological benefit and be inspiring, we decided to start this editorial.
In accordance with this view, I begin this series by telling you about one of my most beloved hobbies: cycling!
Cycling originates from the Greek word kuklos that means cycle, referring to a sequence of a recurring succession of events (Merriam Webster) that can be perpetually reiterated. Although the verb repetition (underlying the mechanism of cycle) may evoke boredom, cycling is instead a very entertaining activity/sport. I learned this point at age 4. In fact, I had just gotten my first bicycle! It was small and red with two extra-wheels on the back. The first cycling battleground was home, cycling from one room to the other of my parents’ house. It was remarkable to experience the simplicity of repeatedly losing and gaining the sight of my family each day. On the bicycle I also felt very relaxed and happy - I was smiling all the time. However, after a few wary indoor rides I started to increment the speed, cycling faster and faster until it started to be incompatible with indoor cycling “rules”. Eventually, pieces of furniture broke down along with a milky tooth and a wounded eye. Clearly, it was time to stop the indoor cycling career!
Some years later, I had the opportunity to expand this early joyful experience to outdoor venues during summertime. It was a moment of relaxation combined with adventure. It was not unlike, say, watching an entertaining adventure movie. In Italy, school vacations last about three months with no interruptions, and this was the time when I first met most of my friends, got to know the environment all-around, and familiarized myself with local animals and trees. Definitively it was one of the best experiences of my life.
Nowadays my relationship with cycling has changed and expanded. I use it regularly to go to work and this also serves as training for my summer competitions. Initially, when I saw people doing it, I did not envy them. They were using it as a sad means of transportation: no matter if it was sunny, cloudy or cold, they did it. The obligation of repetitively using the bicycle seemed so burdensome that it convinced me I would never do the same. Who would want to do that? But things changed when I got my first very attractive bicycle! Right from the first ride I experienced the same feelings as in early times: very happy, relaxed and with the inclination to cycle very fast! If I try to explain why I like it, the main answer would be that, independently of the weather conditions, it reminds me of the sun, the nature and that I feel physically and mentally empowered thereafter. Cycling, greatly improves my mental and physical performance. For example, I am particularly fluent with a third foreign language (i.e. German) or reach better level of thinking just after cycling. In addition, my heart has also gotten stronger (the heart rate heads to 50-40 bpm) and my muscles work more efficiently. Some obvious consequences of this are that I can enjoy: 1) eating more and 2) climbing mountains with discouraging (for most not-trained riders) slopes!
In other words, cycling has made me a slightly different and, probably, better man, even though I now look like those people who I did not envy initially. Whether cycling is a good thing or not is not meant to be the final message. But maybe the message of this story is that if you do meet a Maestro in life, take notice, as that may be what you would really like to do, as well.
Dr. Kelly G. Lambert, former IBNS President, was at Randolph-Macon College for 28 years (Macon and Joan Brock Professor of Neuroscience, Chair of the Psychology Dept (17 years) and Co-Director of the Office of Undergraduate Research (20 years), worked to build a behavioral neuroscience laboratory for undergraduates and, just three years ago, a behavioral neuroscience major that she directed until leaving the institution. Although Kelly never thought she would move, a dear friend and colleague, Craig Kinsley, who was at the University of Richmond passed away last January and they reached out to her to apply for the position. It was a tough decision but Kelly decided to make the move (she was already close by) and, consequently, she is busy building a new lab that will engage undergraduates as they explore experience-based neuroplasticity in rodent models-and she still hopes to continue with the field work at the Dumond Conservancy Primate satellite lab in Miami. Dr. Lambert's new title at UR is Professor of Behavioral Neuroscience and she is looking forward to working on neuroscience curricula/programs there as well. According to Dr. Lambert: "So, it is exciting to be on a new adventure, but very bittersweet being in the former office of such a dear friend who is no longer with us. We never know where our careers will take us!"
Kim Gerecke is very excited to be joining the faculty in the department of Psychology at Randolph-Macon college this Fall. They have a thriving Behavioral Neuroscience program, and she has long been impressed with the work that she have seen from their faculty and students who have presented their research at IBNS over the years. She is especially looking forward to being able to collaborate with fellow members Massimo Bardi and Kelly Lambert, who will be nearby at the University of Richmond. Dr. Gerecke stated, "Randolph-Macon has had a special place in my heart for some time; during my Masters' with Craig Kinsley at the University of Richmond we frequently went to RMC to do research with Kelly Lambert. I feel very honored and grateful to be joining such a thriving program, with wonderful students and faculty."