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Researchers
  • Dr.  Yonatan Kupchik
Dr Yonatan Kupchik
 
Introduction
Motivation is an essential component of our life. Almost everything we do is determined by our motivation to do it. Normally, motivated behavior is the driving force behind adaptive behaviors that maximize our chances of reinforcement and survival. However, losing control over motivated behavior is detrimental and leads to one of the most devastating behavioral disorders – addiction. This may be true not only for drugs of abuse but for natural rewards like palatable food as well.
 
Our lab is interested in understanding what happens in the brain that turns normal motivated behavior into an addiction. We investigate this by combining electrophysiology with behavioral models of drug addiction and obesity, optogenetics, chemogenetics and immunohistochemistry to target and manipulate specific circuits in the reward system and evaluate synaptic plasticity in addiction and obesity.
 
 
Research
The nucleus accumbens (NAc) and the ventral pallidum (VP) are two regions in the basal ganglia that are deeply involved in the execution of motivated behavior, and uncontrolled motivated behavior is tightly linked with permanent synaptic changes in these two regions (Fig. 1-2).
 
Figure 1  Chronic cocaine causes
Figure 2  After extinction of cocaine
Figure 1 – Chronic cocaine causes permanent potentiation of glutamatergic synapses in the NAc and a relapse event causes a further rapid potentiation. After two weeks of cocaine self-administration followed by two weeks of extinction (no cocaine available) glutamate neurotransmission in the NAc, measured as the AMPA/NMDA ratio, is potentiated (compare extinction (Ext.) to yoked saline (Sal.)). When a relapse event is induced by a cocaine-associated cue, a further potentiation is observed (Reins.). ​
Figure 2 – After extinction of cocaine self-administration NAc input to the VP lacks the ability to undergo long-term depression.  Time course of the LTD generated in yoked saline rats after a high-frequency stimulation protocol. Cocaine-extinguished rats did not show LTD after the same protocol.
 
 
 
 
 
The NAc and the VP receive various inputs and project to many brain regions and thus neurons of the NAc and VP participate in many different neural circuits. Moreover, the NAc and the VP are themselves interconnected in a complex manner. Recent studies show that synaptic plasticity in the NAc after exposure to drugs is not homogenous and occurs at specific synapses. Thus, loss of control on motivated behavior is likely to be mediated by subpopulations in the NAc and the VP that form dedicated microcircuits. Identifying and targeting these specific microcircuits and the synaptic changes therein leading to addictive behavior is therefore crucial.
 
Figure 3  A typical VP neuron

 

 

 

 

 

 

 

 

 

 

Figure 3 – A typical VP neuron.

Note the long aspiny processes.​

 
Our lab is interested in the plasticity occurring at specific synapses that may underlie the transition from normal motivation to pathological reward seeking, such as that seen in drug addiction and compulsive overeating. We do this by identifying the relevant microcircuits, detecting synaptic changes in animal models of pathological motivation and targeting the aberrant synapses in vivo in attempt to reverse the addictive behavior.
 
Figure 4  General strategy for studying microcircuits involved in addiction

Figure 5  An example of a VP neuron containing the retrograde tracer Retrobeads

 

Figure 5 – An example of a VP neuron containing the retrograde tracer Retrobeads.

Figure 4 – General strategy for studying microcircuits involved in addiction.

By using Channelrhodopsin in the NAc and retrobeads in various targts of the VP we can study specific projection neurons in the VP and their specific input from the NAc.​

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Selected publications
Stefanik, M.T., Kupchik, Y.M., Kalivas, P.W. (in press) Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior. Brain Structure and Function.
 
Smith, A.W., Kupchik, Y.M., Gipson, C.D., Scofield, M.D., Kalivas, P.W. (2014) Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nature Neuroscience, 2014 Oct 19. doi: 10.1038/nn.3846.
 
Kupchik, Y.M., Scofield, M.D., Rice, K.C., Cheng, K., Roques, B.P., and Kalivas, P.W. (2014) Cocaine dysregulates opioid gating of GABA neurotransmission in the ventral pallidum. J. Neuroscience, 34(3):1057-66.
 
Stefanik, M.T., Kupchik, Y.M., Brown, R.M., and Kalivas, P.W. (2013) Optogenetic evidence that pallidal projections, not nigral projections, from the nucleus accumbens core are necessary for reinstating cocaine seeking. J. Neuroscience, 33(34):13654-13662. (Featured article)
 
Stefanik, M.T., Kupchik, Y.M., Brown, R.M., and Kalivas, P.W. (2013) Optogenetic evidence that pallidal projections, not nigral projections, from the nucleus accumbens core are necessary for reinstating cocaine seeking. J. Neuroscience, 33(34):13654-13662. (Featured article)
 
Gipson, C.D.*, Kupchik, Y.M.*, Shen, H.*, Reissner, K.J., Thomas, C.A., and Kalivas, P.W. (2013) Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron, Mar 6;77(5):867-72. (* - equal contribution).
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     • Highlighted by NIDA Notes.
 
Kupchik, Y.M#., and Kalivas, P.W. (2012) The rostral subcommissural ventral pallidum is a mix of ventral pallidal neurons and neurons from adjacent areas: an electrophysiological study. Brain Structure and Function, doi: 10.1007/s00429-012-0471-9. (# - corresponding author)
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Stefanik, M., Moussawi, K., Kupchik, Y.M., Smith, K., Miller, R., Huff, M., Deisseroth, K., Kalivas, P.W., and LaLumiere, R. (2013) Optogenetic inhibition of cocaine seeking in rats. Addiction Biology, Jan;18(1):50-3
 
Kupchik, Y.M.#, Moussawi, K., Tang, X.C., Wang, X., Kalivas, B.C., Kolokithas, R., Ogburn, K.B., and Kalivas, P.W. (2012) The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biological Psychiatry, Jun 1;71(11):978-86. (# - corresponding author)
     • Highlighted by NIDA Notes.
 
Kupchik, Y.M., Barchad-Avitzur, O., Wess, J., Ben-Chaim, Y., Parnas, I., and Parnas, H. (2011) A novel fast mechanism for GPCRs-mediated signal transduction – control of neurotransmitter release. Journal of Cell Biology, 192(1):137-51. (Featured article)
 
Kupchik, Y.M., Rashkovan, G., Ohana, L., Keren-Raifman, T., Dascal, N., Parnas, H., and Parnas, I. (2008). Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release. PNAS, 105 (11);4435-4440.
 
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