Papers by Yonatan Kupchik
The ventral pallidum (VP), a major component of the basal ganglia, plays a critical role in motiv... more The ventral pallidum (VP), a major component of the basal ganglia, plays a critical role in motivational disorders. It sends projections to many different brain regions but it is not yet known whether and how these projections differ in their cellular properties, gene expression patterns, connectivity and role in reward seeking. In this study, we focus on four major outputs of the VP - to the lateral hypothalamus (LH), ventral tegmental area (VTA), mediodorsal thalamus (MDT), and lateral habenula (LHb) - and examine the differences between them in 1) baseline gene expression profiles using projection-specific RNA-sequencing; 2) physiological parameters using whole-cell patch cl& and 3) their influence on cocaine reward using chemogenetic tools. We show that these four VP efferents differ in all three aspects and highlight specifically differences between the projections to the LH and the VTA. These two projections originate largely from separate populations of neurons, express disti...
Neuroscience & Biobehavioral Reviews
The Journal of Neuroscience
BackgroundA major driver of obesity is the increasing palatability of processed foods. Although t... more BackgroundA major driver of obesity is the increasing palatability of processed foods. Although the reward system promotes the consumption of palatable food it is not yet understood whether and how pathology in the reward system may drive obesity. Here, we examine how chronic high-fat-high-sugar (HFHS) diet changes the physiology of the ventral pallidum (VP), a key hub in the reward system, how obesity-prone mice differ from obesity-resistant mice in their VP physiology, and identify metaplasticity in the VP as a possible marker for the predisposition to overeat.MethodsMale C57bl6/J wildtype mice first had 10-12 weeks of chronic exposure to HFHS or chow diet in their homecages. Then, mice were sacrificed and we recorded from single VP neurons in acute slices using the whole-cell patch clamp technique.ResultsChronic HFHS diet decreased the excitability of VP neurons, but without major change in synaptic inhibitory input. Within the HFHS group, obesity-prone (OP, top 33% weight gainer...
The Journal of Neuroscience
The Journal of Neuroscience
Addiction Biology
Obesity results from overconsumption of energy, partly because of the inability to refrain from h... more Obesity results from overconsumption of energy, partly because of the inability to refrain from highly palatable rewarding foods. Even though palatable food is available to everyone, only a fraction of the population develops obesity. We previously showed that following chronic exposure to highly palatable food animals that gained the most weight also showed addictive-like motivation to seek for palatable food. An important question remains-is this extreme, addictive-like, motivation to consume palatable food the cause or the consequence of diet-induced obesity? Here, we show that obesity-prone (OP) mice exhibit higher motivation for palatable food consumption compared with obesity-resistant mice even before developing obesity, but that the full manifestation of this high motivation to eat is expressed only after chronic exposure to high-fat-high-sugar (HFHS) diet. HFHS diet also impairs performance in the operant food-seeking task selectively in OP mice, an impairment that persists even after 2 weeks of abstinence from HFHS food. Overall, our data suggest that while some aspects of food motivation are high in OP mice already before developing obesity, the chronic exposure to HFHS food accentuates it and drives the development of obesity.
Journal of Neuroscience, 2016
Distinct populations of D1-and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs)... more Distinct populations of D1-and D2-dopamine receptor-expressing medium spiny neurons (D1-/D2-MSNs) comprise the nucleus accumbens, and activity in D1-MSNs promotes, whereas activity in D2-MSNs inhibits, motivated behaviors. We used chemogenetics to extend D1-/D2-MSN cell specific regulation to cue-reinstated cocaine seeking in a mouse model of self-administration and relapse, and found that either increasing activity in D1-MSNs or decreasing activity in D2-MSNs augmented cue-induced reinstatement. Both D1-and D2-MSNs provide substantial GABAergic innervation to the ventral pallidum, and chemogenetic inhibition of ventral pallidal neurons blocked the augmented reinstatement elicited by chemogenetic regulation of either D1-or D2-MSNs. Because D1-and D2-MSNs innervate overlapping populations of ventral pallidal neurons, we next used optogenetics to examine whether changes in synaptic plasticity in D1-versus D2-MSN GABAergic synapses in the ventral pallidum could explain the differential regulation of VP activity. In mice trained to self-administer cocaine, GABAergic LTD was abolished in D2-, but not in D1-MSN synapses. A opioid receptor antagonist restored GABA currents in D2-, but not D1-MSN synapses of cocaine-trained mice, indicating that increased enkephalin tone on presynaptic opioid receptors was responsible for occluding the LTD. These results identify a behavioral function for D1-MSN innervation of the ventral pallidum, and suggest that losing LTD GABA in D2-MSN, but not D1-MSN input to ventral pallidum may promote cue-induced reinstatement of cocaine-seeking.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information ... more The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goaldirected behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking.Anumber of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These druginduced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relaps...
Biological Psychiatry, 2015
There is increasing evidence that the pathological overeating underlying some forms of obesity is... more There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction.
The prevalence and impact of drug addiction on society are staggering. The abuse of alcohol, toba... more The prevalence and impact of drug addiction on society are staggering. The abuse of alcohol, tobacco, and illicit drugs accounts for approximately 10% of the global burden of disease, and for the United States, it is estimated that substance use disorders affect 20.4 million individuals. 1 Despite the deleterious economic and social consequences of drug use, approved medications to treat substance use disorders are few or absent depending on the drug. We and others have explored the possibility that dysregulation in prefrontal and allocortical (amygdala and hippocampus) glutamatergic inputs to the basal ganglia may be a mechanism responsible for relapse that is shared between classes of addictive drugs, as well as other disorders characterized by maladaptive compulsive behavior. Herein, we describe the benchto-bedside chronology of preclinical discovery and clinical trials that led to the cysteine prodrug N-acetylcysteine being evaluated for the treatment of substance abuse and compulsive disorders. Drug addiction is a chronic brain disorder characterized by compulsive drug use that occurs at the expense of other biologically adaptive activities. The transition from casual to compulsive drug use and the enduring propensity to relapse is maintained by longlasting neuroadaptations in specific brain circuits. For example, it is well established that all drugs of abuse enhance dopamine neurotransmission to reinforce and establish drug-seeking behavior. Although less thoroughly studied, we and others have shown that the enduring vulnerability to relapse to drug use involves the recruitment of glutamatergic projections to the ventral striatum, in particular the nucleus accumbens, and is associated with enduring changes in glutamatergic synaptic transmission. Glutamatergic inputs from the amygdala, hippocampus, and prefrontal cortex to the accumbens regulate adaptive behavioral responses by integrating environmental stimuli with memories of related experiences. 2 Thus, by producing enduring changes in glutamatergic synapses in the accumbens, longterm use of addictive drugs impairs the ability of an individual to inhibit drug seeking and use, ultimately producing the persistent relapsing disorder that characterizes drug addiction. Animal models of drug addiction have shown that drug seeking is associated with increased glutamate release from prefrontal projections into the nucleus accumbens. When large amounts of glutamate are released, the excess spills out of the synaptic cleft and activates extrasynaptic glutamate receptors (Figure). Demonstrating spillover of synaptically released glutamate in animals trained to self-administer cocaine, heroin, nicotine, or alcohol was an important indication that alterations in glutamatergic synapses might be re
Nature Neuroscience, 2014
Relapse to cocaine use necessitates remodeling excitatory synapses in the nucleus accumbens, and ... more Relapse to cocaine use necessitates remodeling excitatory synapses in the nucleus accumbens, and synaptic reorganization requires matrix metalloproteinase (MMP) degradation of the extracellular matrix proteins. We found enduring increases in MMP-2 activity in rats after withdrawal from self-administered cocaine and transient increases in MMP-9 during cue-induced cocaine relapse. Cue-induced heroin and nicotine relapse increased MMP activity, and increased MMP activity was required for both cocaine relapse and relapse-associated synaptic plasticity. Vulnerability to relapse is a defining characteristic of drug addiction, and controlling relapse a primary therapeutic goal in treating addiction 1. The inability to control drug use is associated with neuropathologies in cortical regulation of the striatal circuitry, including constitutive potentiation of cortical glutamatergic synapses in the nucleus accumbens core (NAcore) 2, 3 , and further transient synaptic potentiation (t-SP) when relapse is initiated by cocaine injection or cocaine-associated cues 4, 5. Although these studies show that synaptic potentiation at glutamatergic synapses in NAcore is required for relapse to cocaine seeking, it is not understood how the long-lasting potentiation after withdrawal is stabilized, or how relapse-associated t-SP is initiated. Synaptic remodeling depends on the extracellular matrix (ECM), which is a proteinacious network ensheathing synapses that is regulated by Zn 2+-dependent endopeptidases called matrix metalloproteinases (MMPs) 6. MMP-2 and-9 make up the gelatinase subfamily 7 that regulates synaptic structure and physiology by proteolytically processing ECM glycoproteins to initiate glutamate receptor trafficking and actin polymerization 6, 8. Using a relapse model of cocaine, heroin and nicotine self-administration and reinstatement in rats, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Neuron, 2013
Cocaine addiction is characterized by long-lasting vulnerability to relapse arising because neutr... more Cocaine addiction is characterized by long-lasting vulnerability to relapse arising because neutral environmental stimuli become associated with drug use and then act as cues that induce relapse. It is not known how cues elicit cocaine seeking, and why cocaine seeking is more difficult to regulate than seeking a natural reward. We found that cocaine-associated cues initiate cocaine seeking by inducing a rapid, transient increase in dendritic spine size and synaptic strength in the nucleus accumbens. These changes required neural activity in the prefrontal cortex. This is not the case when identical cues were associated with obtaining sucrose, which did not elicit changes in spine size or synaptic strength. The marked cue-induced synaptic changes in the accumbens were correlated with the intensity of cocaine, but not sucrose seeking, and may explain the difficulty addicts experience in managing relapse to cocaine use.
Journal of Neuroscience, 2013
The core subcompartment of the nucleus accumbens (NAcore) contributes significantly to behavioral... more The core subcompartment of the nucleus accumbens (NAcore) contributes significantly to behavioral responses following motivationally relevant stimuli, including drug-induced, stress-induced, and cue-induced reinstatement of cocaine seeking. Projections from NAcore that could carry information necessary to initiate reinstated cocaine seeking include outputs via the indirect pathway to the dorsolateral subcompartment of the ventral pallidum (dlVP) and through the direct pathway to the medial substantia nigra (SN). Here we used an optogenetic strategy to determine whether the dlVP or nigral projections from the NAcore are necessary for cocaine seeking initiated by a cocaine and conditioned cue combination in rats extinguished from cocaine self-administration. Rats were pretreated in the NAcore with an adeno-associated virus expressing the inhibitory opsin archaerhodopsin, and fiber-optic cannulae were implanted above the indirect pathway axon terminal field in the dlVP, or the direct pathway terminal field in the SN. Inhibiting the indirect pathway to the dlVP, but not the direct pathway to the SN, prevented cocaine-plus-cue-induced reinstatement. We also examined projections back to the NAcore from the ventral tegmental area (VTA) and dlVP. Inhibiting the dlVP to NAcore projection did not alter, while inhibiting VTA afferents abolished reinstated cocaine seeking. Localization of green fluorescent protein reporter expression and whole-cell patch electrophysiology were used to verify opsin expression. These data reveal a circuit involving activation of VTA inputs to the NAcore and NAcore projections through the indirect pathway to the dlVP as critical for cocaine-plus-cue-induced reinstatement of cocaine seeking.
Nature Neuroscience, 2015
It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their informat... more It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.
Brain Structure and Function
Animal models of relapse reveal that the motivation to seek drug is regulated by enduring morphol... more Animal models of relapse reveal that the motivation to seek drug is regulated by enduring morphological and physiological changes in the nucleus accumbens, as well as transient synaptic potentiation in the accumbens core (NAcore) that parallels drug-seeking behavior. The current study sought to examine the link between the behavioral and synaptic consequences of cue-induced cocaine seeking by optically silencing glutamatergic afferents to the NAcore from the prelimbic cortex (PL). Adeno-associated virus coding for the inhibitory opsin archaerhodopsin was microinjected into PL, and optical fibers were targeted to NAcore. Animals were trained to self-administer cocaine followed by extinction training, and then underwent cue-induced reinstatement in the presence or absence of 15 min of optically induced inhibition of PL fibers in NAcore. Inhibiting the PL-to-NAcore projection blocked reinstated behavior and was paralleled by decreased dendritic spine head diameter and AMPA/NMDA ratio r...
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these proje... more The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-de...
Drug and Alcohol Dependence, 2015
Journal of Neuroscience, 2014
The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these proje... more The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a ␦ and opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in rewardrelated behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse.
Uploads
Papers by Yonatan Kupchik