Publications by authors named "Yanhua H Huang"

49 Publications

Cocaine-induced projection-specific and cell type-specific adaptations in the nucleus accumbens.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Cocaine craving, seeking, and relapse are mediated, in part, by cocaine-induced adaptive changes in the brain reward circuits. The nucleus accumbens (NAc) integrates and prioritizes different emotional and motivational inputs to the reward system by processing convergent glutamatergic projections from the medial prefrontal cortex, basolateral amygdala, ventral hippocampus, and other limbic and paralimbic brain regions. Medium spiny neurons (MSNs) are the principal projection neurons in the NAc, which can be divided into two major subpopulations, namely dopamine receptor D1- versus D2-expressing MSNs, with complementing roles in reward-associated behaviors. After cocaine experience, NAc MSNs exhibit complex and differential adaptations dependent on cocaine regimen, withdrawal time, cell type, location (NAc core versus shell), and related input and output projections, or any combination of these factors. Detailed characterization of these cellular adaptations has been greatly facilitated by the recent development of optogenetic/chemogenetic techniques combined with transgenic tools. In this review, we discuss such cell type- and projection-specific adaptations induced by cocaine experience. Specifically, (1) D1 and D2 NAc MSNs frequently exhibit differential adaptations in spinogenesis, glutamatergic receptor trafficking, and intrinsic membrane excitability, (2) cocaine experience differentially changes the synaptic transmission at different afferent projections onto NAc MSNs, (3) cocaine-induced NAc adaptations exhibit output specificity, e.g., being different at NAc-ventral pallidum versus NAc-ventral tegmental area synapses, and (4) the input, output, subregion, and D1/D2 cell type may together determine cocaine-induced circuit plasticity in the NAc. In light of the projection- and cell-type specificity, we also briefly discuss ensemble and circuit mechanisms contributing to cocaine craving and relapse after drug withdrawal.
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http://dx.doi.org/10.1038/s41380-021-01112-2DOI Listing
May 2021

AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses.

J Neurosci 2021 Mar 12;41(9):1996-2011. Epub 2021 Jan 12.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in GluN2B-containing NMDA receptors (NMDARs). After drug withdrawal, some of these synapses mature by recruiting AMPARs, strengthening the newly established synaptic transmission. Silent synapse generation and maturation are two consecutive cellular steps through which NAc circuits are profoundly remodeled to promote cue-induced cocaine seeking after drug withdrawal. However, the basic cellular processes that mediate these two critical steps remains underexplored. Using a combination of electrophysiology, viral-mediated gene transfer, and confocal imaging in male rats as well as knock-in (KI) mice of both sexes, our current study characterized the dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation of silent synapses not only required synaptic insertion of GluN2B-containing NMDARs, but also, counterintuitively, involved insertion of AMPARs, which subsequently internalized, resulting in the AMPAR-silent state on withdrawal day 1. Furthermore, GluN2B NMDARs functioned to maintain these cocaine-generated synapses in the AMPAR-silent state during drug withdrawal, until they were replaced by nonGluN2B NMDARs, a switch that allowed AMPAR recruitment and maturation of silent synapses. These results reveal dynamic interactions between AMPARs and NMDARs during the generation and maturation of silent synapses after cocaine experience and provide a mechanistic basis through which new synaptic contacts and possibly new neural network patterns created by these synapses can be manipulated for therapeutic benefit. Studies over the past decade reveal a critical role of AMPA receptor-silent, NMDA receptor-containing synapses in forming cocaine-related memories that drive cocaine relapse. However, it remains incompletely understood how AMPA and NMDA receptors traffic at these synapses during their generation and maturation. The current study characterizes a two-step AMPA receptor trafficking cascade that contributes to the generation of silent synapses in response to cocaine experience, and a two-step NMDA receptor trafficking cascade that contributes to the maturation of these synapses after cocaine withdrawal. These results depict a highly regulated cellular procedure through which nascent glutamatergic synapses are generated in the adult brain after drug experience and provide significant insight into the roles of glutamate receptors in synapse formation and maturation.
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http://dx.doi.org/10.1523/JNEUROSCI.1918-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939090PMC
March 2021

Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex.

Pain 2021 May;162(5):1322-1333

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.

Abstract: Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become "unsilenced" by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
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http://dx.doi.org/10.1097/j.pain.0000000000002149DOI Listing
May 2021

Cocaine-induced neural adaptations in the lateral hypothalamic melanin-concentrating hormone neurons and the role in regulating rapid eye movement sleep after withdrawal.

Mol Psychiatry 2020 Oct 22. Epub 2020 Oct 22.

Departments of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic drug use. Notably, rapid eye movement (REM) sleep regulates emotional memory, and persistent REM sleep impairment after cocaine withdrawal negatively impacts relapse-like behaviors in rats. However, it is not understood how cocaine experience may alter REM sleep regulatory machinery, and what may serve to improve REM sleep after withdrawal. Here, we focus on the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH), which regulate REM sleep initiation and maintenance. Using adult male Sprague-Dawley rats trained to self-administer intravenous cocaine, we did transcriptome profiling of LH MCH neurons after long-term withdrawal using RNA-sequencing, and performed functional assessment using slice electrophysiology. We found that 3 weeks after withdrawal from cocaine, LH MCH neurons exhibit a wide range of gene expression changes tapping into cell membrane signaling, intracellular signaling, and transcriptional regulations. Functionally, they show reduced membrane excitability and decreased glutamatergic receptor activity, consistent with increased expression of voltage-gated potassium channel gene Kcna1 and decreased expression of metabotropic glutamate receptor gene Grm5. Finally, chemogenetic or optogenetic stimulations of LH MCH neural activity increase REM sleep after long-term withdrawal with important differences. Whereas chemogenetic stimulation promotes both wakefulness and REM sleep, optogenetic stimulation of these neurons in sleep selectively promotes REM sleep. In summary, cocaine exposure persistently alters gene expression profiles and electrophysiological properties of LH MCH neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhances REM sleep quality and quantity after long-term withdrawal.
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http://dx.doi.org/10.1038/s41380-020-00921-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060355PMC
October 2020

Cocaine Triggers Astrocyte-Mediated Synaptogenesis.

Biol Psychiatry 2021 02 25;89(4):386-397. Epub 2020 Aug 25.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Synaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, α2δ-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens shell (NAcSh).

Methods: Using multidisciplinary approaches including astrocyte Ca imaging, genetic mouse lines, viral-mediated gene transfer, and operant behavioral procedures, we monitor the response of NAcSh astrocytes to cocaine administration and examine the role of astrocytic TSP-α2δ-1 signaling in cocaine-induced silent synapse generation as well as the behavioral impact of astrocyte-mediated synaptogenesis and silent synapse generation.

Results: Cocaine administration acutely increases Ca events in NAcSh astrocytes, while decreasing astrocytic Ca blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of α2δ-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and synapse generation in NAcSh decreases cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction.

Conclusions: These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.
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http://dx.doi.org/10.1016/j.biopsych.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854999PMC
February 2021

Cortical and Thalamic Interaction with Amygdala-to-Accumbens Synapses.

J Neurosci 2020 09 6;40(37):7119-7132. Epub 2020 Aug 6.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

The nucleus accumbens shell (NAcSh) regulates emotional and motivational responses, a function mediated, in part, by integrating and prioritizing extensive glutamatergic projections from limbic and paralimbic brain regions. Each of these inputs is thought to encode unique aspects of emotional and motivational arousal. The projections do not operate alone, but rather are often activated simultaneously during motivated behaviors, during which they can interact and coordinate in shaping behavioral output. To understand the anatomic and physiological bases underlying these interprojection interactions, the current study in mice of both sexes focused on how the basolateral amygdala projection (BLAp) to the NAcSh regulates, and is regulated by, projections from the medial prefrontal cortex (mPFCp) and paraventricular nucleus of the thalamus (PVTp). Using a dual-color SynaptoTag technique combined with a backfilling spine imaging strategy, we found that all three afferent projections primarily targeted the secondary dendrites of NAcSh medium spiny neurons, forming putative synapses. We detected a low percentage of BLAp contacts closely adjacent to mPFCp or PVTp presumed synapses, and, on some rare occasions, the BLAp formed heterosynaptic interactions with mPFCp or PVTp profiles or appeared to contact the same spines. Using dual-rhodopsin optogenetics, we detected signs of dendritic summation of BLAp with PVTp and mPFCp inputs. Furthermore, high-frequency activation of BLAp synchronous with the PVTp or mPFCp resulted in a transient enhancement of the PVTp, but not mPFCp, transmission. These results provide anatomic and functional indices that the BLAp interacts with the mPFCp and PVTp for informational processing within the NAcSh. The nucleus accumbens regulates emotional and motivational responses by integrating extensive glutamatergic projections, but the anatomic and physiological bases on which these projections integrate and interact remain underexplored. Here, we used dual-color synaptic markers combined with backfilling of nucleus accumbens medium spiny neurons to reveal some unique anatomic alignments of presumed synapses from the basolateral amygdala, medial prefrontal cortex, and paraventricular nucleus of thalamus. We also used dual-rhodopsin optogenetics in brain slices, which reveal a nonlinear interaction between some, but not all, projections. These results provide compelling anatomic and physiological mechanisms through which different glutamatergic projections to the nucleus accumbens, and possibly different aspects of emotional and motivational arousal, interact with each other for final behavioral output.
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http://dx.doi.org/10.1523/JNEUROSCI.1121-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480237PMC
September 2020

A Critical Role of Basolateral Amygdala-to-Nucleus Accumbens Projection in Sleep Regulation of Reward Seeking.

Biol Psychiatry 2020 06 9;87(11):954-966. Epub 2019 Nov 9.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Sleep impacts reward-motivated behaviors partly by retuning the brain reward circuits. The nucleus accumbens (NAc) is a reward processing hub sensitive to acute sleep deprivation. Glutamatergic transmission carrying reward-associated signals converges in the NAc and regulates various aspects of reward-motivated behaviors. The basolateral amygdala projection (BLAp) innervates broad regions of the NAc and critically regulates reward seeking.

Methods: Using slice electrophysiology, we measured how acute sleep deprivation alters transmission at BLAp-NAc synapses in male C57BL/6 mice. Moreover, using SSFO (stabilized step function opsin) and DREADDs (designer receptors exclusively activated by designer drugs) (Gi) to amplify and reduce transmission, respectively, we tested behavioral consequences following bidirectional manipulations of BLAp-NAc transmission.

Results: Acute sleep deprivation increased sucrose self-administration in mice and altered the BLAp-NAc transmission in a topographically specific manner. It selectively reduced glutamate release at the rostral BLAp (rBLAp) onto ventral and lateral NAc (vlNAc) synapses, but spared caudal BLAp onto medial NAc synapses. Furthermore, experimentally facilitating glutamate release at rBLAp-vlNAc synapses suppressed sucrose reward seeking. Conversely, mimicking sleep deprivation-induced reduction of rBLAp-vlNAc transmission increased sucrose reward seeking. Finally, facilitating rBLAp-vlNAc transmission per se did not promote either approach motivation or aversion.

Conclusions: Sleep acts on rBLAp-vINAc transmission gain control to regulate established reward seeking but does not convey approach motivation or aversion on its own.
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http://dx.doi.org/10.1016/j.biopsych.2019.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210061PMC
June 2020

Calcineurin Promotes Neuroplastic Changes in the Amygdala Associated with Weakened Cocaine-Cue Memories.

J Neurosci 2020 02 20;40(6):1344-1354. Epub 2019 Dec 20.

Department of Psychiatry,

Interfering with memory reconsolidation or inducing memory extinction are two approaches for weakening maladaptive memories in disorders such as addiction and post-traumatic stress disorder. Both extinction and reconsolidation are regulated by intracellular protein kinases and phosphatases, and interfering with these signaling molecules can alter memory strength. The calcium-dependent protein phosphatase, calcineurin (CaN), has been implicated in both the consolidation and extinction of fear memories. However, the role of CaN in regulating drug-cue associative memories has not been investigated. Prior studies have demonstrated that plasticity at thalamo-lateral amygdala (T-LA) synapses is critically involved in the regulation of cocaine-cue memories. Therefore, in the present study, we tested the effects of LA administration of an activator of CaN, chlorogenic acid (CGA), on behavioral and electrophysiological indices of cocaine cue memory reconsolidation and extinction. Male, Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. The cue memory was then either briefly reactivated, extinguished, or not manipulated, followed immediately by LA infusion of CGA. Rats were tested 24 h later for cue-induced reinstatement, or LA slices were prepared for electrophysiological recordings. We found that intra-LA infusions of CGA following cue extinction or reconsolidation reduced cue-induced reinstatement, which was blocked by co-infusion of the CaN inhibitor, FK-506. Similarly, CGA infusions following cue re-exposure significantly attenuated EPSC amplitude at T-LA synapses, suggesting that CaN affects cocaine-cue memory reconsolidation and extinction by altering T-LA synaptic strength. Therefore, CaN signaling in the LA may represent a novel target for disrupting cocaine-associated memories to reduce relapse. Repetitive drug use induces synaptic plasticity that underlies the formation of long-lasting associative memories for environmental cues paired with the drug. We previously identified thalamo-amygdala synapses (T-LA) that project via the interal capsule, as an important locus for the regulation of cocaine-cue memories. These synapses are strengthened by repeated cocaine-cue pairings, but this is reversed by extinction training or by optogenetic induction of long-term depression (LTD). Here, we demonstrate that activating calcineurin, a calcium-dependent phosphatase, following the reactivation or extinction of a cocaine-cue memory, induces LTD-like changes at T-LA synapses, and a corresponding decrease in cue-induced reinstatement, suggesting that calcineurin may be a potential therapeutic target for relapse prevention.
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http://dx.doi.org/10.1523/JNEUROSCI.0453-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002139PMC
February 2020

Silent synapses dictate cocaine memory destabilization and reconsolidation.

Nat Neurosci 2020 01 2;23(1):32-46. Epub 2019 Dec 2.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.

Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, on memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 h later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are timed by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.
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http://dx.doi.org/10.1038/s41593-019-0537-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930359PMC
January 2020

Chronic sleep fragmentation enhances habenula cholinergic neural activity.

Mol Psychiatry 2021 03 12;26(3):941-954. Epub 2019 Apr 12.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Sleep is essential to emotional health. Sleep disturbance, particularly REM sleep disturbance, profoundly impacts emotion regulation, but the underlying neural mechanisms remain elusive. Here we show that chronic REM sleep disturbance, achieved in mice by chronic sleep fragmentation (SF), enhanced neural activity in the medial habenula (mHb), a brain region increasingly implicated in negative affect. Specifically, after a 5-day SF procedure that selectively fragmented REM sleep, cholinergic output neurons (ChNs) in the mHb exhibited increased spontaneous firing rate and enhanced firing regularity in brain slices. The SF-induced firing changes remained intact upon inhibition of glutamate, GABA, acetylcholine, and histamine receptors, suggesting cell-autonomous mechanisms independent of synaptic transmissions. Moreover, the SF-induced hyperactivity was not because of enhanced intrinsic membrane excitability, but was accompanied by depolarized resting membrane potential in mHb ChNs. Furthermore, inhibition of TASK-3 (KCNK9) channels, a subtype of two-pore domain K channels, mimicked the SF effects by increasing the firing rate and regularity, as well as depolarizing the resting membrane potential in mHb ChNs in control-sleep mice. These effects of TASK-3 inhibition were absent in SF mice, suggesting reduced TASK-3 activity following SF. By contrast, inhibition of small-conductance Ca-activated K (SK) channels did not produce similar effects. Thus, SF compromised TASK-3 function in mHb ChNs, which likely led to depolarized resting membrane potential and increased spontaneous firing. These results not only demonstrate that selective REM sleep disturbance leads to hyperactivity of mHb ChNs, but also identify a key molecular substrate through which REM sleep disturbance may alter affect regulation.
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http://dx.doi.org/10.1038/s41380-019-0419-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790161PMC
March 2021

Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2.

J Neurosci 2019 06 8;39(24):4657-4667. Epub 2019 Apr 8.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, and

The circadian transcription factor neuronal PAS domain 2 (NPAS2) is linked to psychiatric disorders associated with altered reward sensitivity. The expression of is preferentially enriched in the mammalian forebrain, including the nucleus accumbens (NAc), a major neural substrate of motivated and reward behavior. Previously, we demonstrated that downregulation of NPAS2 in the NAc reduces the conditioned behavioral response to cocaine in mice. We also showed that is preferentially enriched in dopamine receptor 1 containing medium spiny neurons (D1R-MSNs) of the striatum. To extend these studies, we investigated the impact of NPAS2 disruption on accumbal excitatory synaptic transmission and strength, along with the behavioral sensitivity to cocaine reward in a cell-type-specific manner. Viral-mediated knockdown of in the NAc of male and female C57BL/6J mice increased the excitatory drive onto MSNs. Using -tdTomato mice in combination with viral knockdown, we determined these synaptic adaptations were specific to D1R-MSNs relative to non-D1R-MSNs. Interestingly, NAc-specific knockdown of blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSNs. Last, we designed, validated, and used a novel Cre-inducible short-hairpin RNA virus for MSN-subtype-specific knockdown of Cell-type-specific knockdown in D1R-MSNs, but not D2R-MSNs, in the NAc reduced cocaine conditioned place preference. Together, our results demonstrate that NPAS2 regulates excitatory synapses of D1R-MSNs in the NAc and cocaine reward-related behavior. Drug addiction is a widespread public health concern often comorbid with other psychiatric disorders. Disruptions of the circadian clock can predispose or exacerbate substance abuse in vulnerable individuals. We demonstrate a role for the core circadian protein, NPAS2, in mediating glutamatergic neurotransmission at medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a region critical for reward processing. We find that NPAS2 negatively regulates functional excitatory synaptic plasticity in the NAc and is necessary for cocaine-induced plastic changes in MSNs expressing the dopamine 1 receptor (D1R). We further demonstrate disruption of NPAS2 in D1R-MSNs produces augmented cocaine preference. These findings highlight the significance of cell-type-specificity in mechanisms underlying reward regulation by NPAS2 and extend our knowledge of its function.
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http://dx.doi.org/10.1523/JNEUROSCI.2233-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561687PMC
June 2019

Cholinergic system in sleep regulation of emotion and motivation.

Pharmacol Res 2019 05 17;143:113-118. Epub 2019 Mar 17.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, 15219, PA, United States. Electronic address:

Sleep profoundly regulates our emotional and motivational state of mind. Human brain imaging and animal model studies are providing initial insights on the underlying neural mechanisms. Here, we focus on the brain cholinergic system, including cholinergic neurons in the basal forebrain, ventral striatum, habenula, and brain stem. Although much is learned about cholinergic regulations of emotion and motivation, less is known on their interactions with sleep. Specifically, we present an anatomical framework that highlights cholinergic signaling in the integrated reward-arousal/sleep circuitry, and identify the knowledge gaps on the potential roles of cholinergic system in sleep-mediated regulation of emotion and motivation. Sleep impacts every aspect of brain functions. It not only restores cognitive control, but also retunes emotional and motivational regulation [1]. Sleep disturbance is a comorbidity and sometimes a predicting factor for various psychiatric diseases including major depressive disorder, anxiety, post-traumatic stress disorder, and drug addiction [2-9]. Although it is well recognized that sleep prominently shapes emotional and motivational regulation, the underlying neural mechanisms remain elusive. The brain cholinergic system is essential for a diverse variety of functions including cognition, learning and memory, sensory and motor processing, sleep and arousal, reward processing, and emotion regulation [10-14]. Although cholinergic functions in cognition, learning and memory, motor control, and sleep and arousal have been well established, its interaction with sleep in regulating emotion and motivation has not been extensively studied. Here we review current evidence on sleep-mediated regulation of emotion and motivation, and reveal knowledge gaps on potential contributions from the cholinergic system.
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http://dx.doi.org/10.1016/j.phrs.2019.03.013DOI Listing
May 2019

Plasticity at Thalamo-amygdala Synapses Regulates Cocaine-Cue Memory Formation and Extinction.

Cell Rep 2019 01;26(4):1010-1020.e5

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address:

Repeated drug use has long-lasting effects on plasticity throughout the brain's reward and memory systems. Environmental cues that are associated with drugs of abuse can elicit craving and relapse, but the neural circuits responsible for driving drug-cue-related behaviors have not been well delineated, creating a hurdle for the development of effective relapse prevention therapies. In this study, we used a cocaine+cue self-administration paradigm followed by cue re-exposure to establish that the strength of the drug cue association corresponds to the strength of synapses between the medial geniculate nucleus (MGN) of the thalamus and the lateral amygdala (LA). Furthermore, we demonstrate, via optogenetically induced LTD of MGN-LA synapses, that reversing cocaine-induced potentiation of this pathway is sufficient to inhibit cue-induced relapse-like behavior.
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http://dx.doi.org/10.1016/j.celrep.2018.12.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392072PMC
January 2019

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Mol Psychiatry 2019 11 4;24(11):1668-1684. Epub 2018 May 4.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15219, USA.

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.
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http://dx.doi.org/10.1038/s41380-018-0061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215755PMC
November 2019

Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving.

J Neurosci 2018 05 6;38(18):4316-4328. Epub 2018 Apr 6.

Departments of Neuroscience,

In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor-mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal. Here, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug-induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse.
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http://dx.doi.org/10.1523/JNEUROSCI.3291-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932642PMC
May 2018

Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents.

Biol Psychiatry 2018 06 15;83(12):987-996. Epub 2017 Dec 15.

Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; The Jackson Laboratory, Bar Harbor, Maine. Electronic address:

Sleep homeostasis and circadian function are important maintaining factors for optimal health and well-being. Conversely, sleep and circadian disruptions are implicated in a variety of adverse health outcomes, including substance use disorders. These risks are particularly salient during adolescence. Adolescents require 8 to 10 hours of sleep per night, although few consistently achieve these durations. A mismatch between developmental changes and social/environmental demands contributes to inadequate sleep. Homeostatic sleep drive takes longer to build, circadian rhythms naturally become delayed, and sensitivity to the phase-shifting effects of light increases, all of which lead to an evening preference (i.e., chronotype) during adolescence. In addition, school start times are often earlier in adolescence and the use of electronic devices at night increases, leading to disrupted sleep and circadian misalignment (i.e., social jet lag). Social factors (e.g., peer influence) and school demands further impact sleep and circadian rhythms. To cope with sleepiness, many teens regularly consume highly caffeinated energy drinks and other stimulants, creating further disruptions in sleep. Chronic sleep loss and circadian misalignment enhance developmental tendencies toward increased reward sensitivity and impulsivity, increasing the likelihood of engaging in risky behaviors and exacerbating the vulnerability to substance use and substance use disorders. We review the neurobiology of brain reward systems and the impact of sleep and circadian rhythms changes on addiction vulnerability in adolescence and suggest areas that warrant additional research.
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http://dx.doi.org/10.1016/j.biopsych.2017.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972052PMC
June 2018

Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration.

Proc Natl Acad Sci U S A 2017 10 25;114(41):E8750-E8759. Epub 2017 Sep 25.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260;

The basolateral amygdala (BLA) sends excitatory projections to the nucleus accumbens (NAc) and regulates motivated behaviors partially by activating NAc medium spiny neurons (MSNs). Here, we characterized a feedforward inhibition circuit, through which BLA-evoked activation of NAc shell (NAcSh) MSNs was fine-tuned by GABAergic monosynaptic innervation from adjacent fast-spiking interneurons (FSIs). Specifically, BLA-to-NAcSh projections predominantly innervated NAcSh FSIs compared with MSNs and triggered action potentials in FSIs preceding BLA-mediated activation of MSNs. Due to these anatomical and temporal properties, activation of the BLA-to-NAcSh projection resulted in a rapid FSI-mediated inhibition of MSNs, timing-contingently dictating BLA-evoked activation of MSNs. Cocaine self-administration selectively and persistently up-regulated the presynaptic release probability of BLA-to-FSI synapses, entailing enhanced FSI-mediated feedforward inhibition of MSNs upon BLA activation. Experimentally enhancing the BLA-to-FSI transmission in vivo expedited the acquisition of cocaine self-administration. These results reveal a previously unidentified role of an FSI-embedded circuit in regulating NAc-based drug seeking and taking.
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http://dx.doi.org/10.1073/pnas.1707822114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642706PMC
October 2017

Prefrontal Cortex to Accumbens Projections in Sleep Regulation of Reward.

J Neurosci 2016 07;36(30):7897-910

Departments of Psychiatry and

Unlabelled: Sleep profoundly affects the emotional and motivational state. In humans and animals, loss of sleep often results in enhanced motivation for reward, which has direct implications for health risks as well as potential benefits. Current study aims at understanding the mechanisms underlying sleep deprivation (SDe)-induced enhancement of reward seeking. We found that after acute SDe, mice had an increase in sucrose seeking and consumption but not food intake, suggesting a selective enhancement of motivation for reward. In the nucleus accumbens (NAc), a key brain region regulating emotional and motivational responses, we observed a decrease in the ratio of the overall excitatory over inhibitory synaptic inputs onto NAc principle neurons after SDe. The shift was partly mediated by reduced glutamatergic transmission of presynaptic origin. Further analysis revealed that there was selective reduction of the glutamate release probability at the medial prefrontal cortex (mPFC)-to-NAc synapses, but not those from the hippocampus, thalamus, or the basal lateral amygdala. To reverse this SDe-induced synaptic alteration, we expressed the stabilized step function opsin (SSFO) in the mPFC; optogenetic stimulation of SSFO at mPFC-to-NAc projection terminals persistently enhanced the action potential-dependent glutamate release. Intra-NAc optogenetic stimulation of SSFO selectively at mPFC-to-NAc terminals restored normal sucrose seeking in mice after SDe without affecting food intake. These results highlight the mPFC-to-NAc projection as a key circuit-based target for sleep to regulate reward-motivated behaviors.

Significance Statement: Sleep loss, a costly challenge of modern society, has profound physiological and psychological consequences, including altered reward processing of the brain. The current study aims at understanding the mechanisms underlying sleep deprivation-induced enhancement of reward seeking. We identify that the medial prefrontal cortex (mPFC)-to-nucleus accumbens (NAc) glutamatergic transmission is selectively weakened following acute sleep deprivation, whose restoration normalizes reward seeking in sleep-deprived mice. These results suggest a possibility of normalizing sleep deprivation-induced abnormal reward seeking by targeting specific neural projections, and they demonstrate the mPFC-to-NAc glutamatergic projection as a key circuit-based target for sleep to regulate reward-motivated behaviors.
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http://dx.doi.org/10.1523/JNEUROSCI.0347-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961777PMC
July 2016

Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses.

Nat Neurosci 2016 07 30;19(7):915-25. Epub 2016 May 30.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. In an effort to explain this paradox, we found that both drugs induced NMDA receptor-containing, AMPA receptor-silent excitatory synapses, albeit in distinct cell types through opposing cellular mechanisms. Cocaine selectively induced silent synapses in D1-type neurons, likely via a synaptogenesis process, whereas morphine induced silent synapses in D2-type neurons via internalization of AMPA receptors from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses became 'unsilenced' by recruiting AMPA receptors to strengthen excitatory inputs to D1-type neurons, whereas morphine-generated silent synapses were likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell type-specific, opposing mechanisms produced the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.
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http://dx.doi.org/10.1038/nn.4313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925174PMC
July 2016

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection.

Neuropsychopharmacology 2016 08 14;41(9):2399-410. Epub 2016 Apr 14.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.

Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine self-administration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short- and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.
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http://dx.doi.org/10.1038/npp.2016.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946070PMC
August 2016

Sleep Regulates Incubation of Cocaine Craving.

J Neurosci 2015 Sep;35(39):13300-10

Departments of Psychiatry and

After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine self-administration, rats exhibited persistent reduction in nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats during their active (dark) phase of the day, which selectively decreased the fragmentation of REM sleep during their inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depicting the progressive intensification of cocaine seeking after withdrawal. In contrast, experimentally increasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substrate that can be engaged by sleep to regulate cocaine craving and relapse, and demonstrate sleep-based therapeutic opportunities for cocaine addiction. Significance statement: Sleep abnormalities are common symptoms in chronic drug users long after drug withdrawal. These withdrawal-associated sleep symptoms, particularly reduction in total sleep time and deteriorating sleep quality, have been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here we show in rats that the sleep pattern was persistently changed long after withdrawal from cocaine self-administration, and demonstrate that sleep interventions can bidirectionally regulate cocaine craving and seeking after withdrawal. We further demonstrate that glutamatergic synapses in the nucleus accumbens are potential neuronal targets for sleep intervention to influence cocaine craving after withdrawal. These results provide a strong rationale supporting sleep-based therapies for cocaine addiction.
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http://dx.doi.org/10.1523/JNEUROSCI.1065-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588606PMC
September 2015

Silent Synapses Speak Up: Updates of the Neural Rejuvenation Hypothesis of Drug Addiction.

Neuroscientist 2015 Oct 31;21(5):451-9. Epub 2015 Mar 31.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

A transient but prominent increase in the level of "silent synapses"--a signature of immature glutamatergic synapses that contain only NMDA receptors without stably expressed AMPA receptors--has been identified in the nucleus accumbens (NAc) following exposure to cocaine. As the NAc is a critical forebrain region implicated in forming addiction-associated behaviors, the initial discoveries have raised speculations about whether and how these drug-induced synapses mature and potentially contribute to addiction-related behaviors. Here, we summarize recent progress in recognizing the pathway-specific regulations of silent synapse maturation, and its diverse impacts on behavior. We provide an update of the guiding hypothesis--the "neural rejuvenation hypothesis"--with recently emerged evidence of silent synapses in cocaine craving and relapse.
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http://dx.doi.org/10.1177/1073858415579405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675132PMC
October 2015

Increased excitability of lateral habenula neurons in adolescent rats following cocaine self-administration.

Int J Neuropsychopharmacol 2014 Dec 28;18(6). Epub 2014 Dec 28.

Neuroscience Department (Drs Neumann, Ishikawa, Otaka, and Dong), and Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA (Dr Huang); Molecular Neurobiology, European Neuroscience Institute, Göttingen, Germany (Dr Schlüter).

Background: The lateral habenula is a brain region that has been critically implicated in modulating negative emotional states and responses to aversive stimuli. Exposure to addictive drugs such as cocaine negatively impacts affective states, an effect persisting longer than acute drug effects. However, the mechanisms of this effect are poorly understood. We hypothesized that drugs of abuse, such as cocaine, may contribute to drug-induced negative affective states by altering the firing properties of lateral habenula neurons, thus changing the signaling patterns from the lateral habenula to downstream circuits.

Methods: Using whole-cell current-clamp recording of acutely prepared brain slices of rats after various periods of withdrawal from cocaine self-administration, we characterized an important heterogeneous subregion of the lateral habenula based on membrane properties.

Results: We found two major relevant neuronal subtypes: burst firing neurons and regular spiking neurons. We also found that lateral habenula regular spiking neurons had higher membrane excitability for at least 7 days following cocaine self-administration, likely due to a greater membrane resistance. Both the increase in lateral habenula excitability and membrane resistance returned to baseline when tested after a more prolonged period of 45 days of withdrawal.

Conclusion: This is the first study to look at intrinsic lateral habenula neuron properties following cocaine exposure beyond acute drug effects. These results may help to explain how cocaine and other drugs negatively impact affect states.
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http://dx.doi.org/10.1093/ijnp/pyu109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390528PMC
December 2014

Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections.

Neuron 2014 Sep 4;83(6):1453-67. Epub 2014 Sep 4.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address:

Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.
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http://dx.doi.org/10.1016/j.neuron.2014.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295617PMC
September 2014

An unusual suspect in cocaine addiction.

Neuron 2013 Nov;80(4):835-6

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA.

Development of drug addiction is extremely complex, but its initiation can be as simple as the flip-flop of glutamatergic receptor subtypes triggered by an "unusual" type of NMDA receptors, as suggested by Yuan et al. (2013) in this issue of Neuron.
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http://dx.doi.org/10.1016/j.neuron.2013.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883311PMC
November 2013

Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Nat Neurosci 2013 Nov 29;16(11):1644-51. Epub 2013 Sep 29.

1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.
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http://dx.doi.org/10.1038/nn.3533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815713PMC
November 2013

Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens.

J Physiol 2013 Oct 5;591(19):4827-41. Epub 2013 Aug 5.

Y. Dong, Y. Huang: University of Pittsburgh, 210 Langley Hall, Department of Neuroscience, PA 15260, USA.

Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg(-1) day(-1) × 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry.
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http://dx.doi.org/10.1113/jphysiol.2013.262915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800457PMC
October 2013

Cocaine-induced membrane adaptation in the central nucleus of amygdala.

Neuropsychopharmacology 2013 Oct 15;38(11):2240-8. Epub 2013 May 15.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Exposure to drugs of abuse lead to both rewarding effects and the subsequent development of negative affects. The progressive dysregulation of both processes is thought to critically contribute to the addictive state. Whereas cocaine-induced maladaptations in reward circuitry have been extensively examined, the cellular substrates underlying negative affect remain poorly understood. This study focuses on the central nucleus of the amygdala (CeA), a brain region that has been implicated in negative affective states upon withdrawal from chronic cocaine use. We observed that the two major types of CeA neurons, low-threshold bursting (LTB) neurons and regular spiking (RS) neurons, exhibited different sensitivity to corticotrophin-releasing factor (CRF), a stress hormone that has been implicated in negative affect during drug withdrawal. Furthermore, LTB and RS neurons developed opposite membrane adaptations following short-term (5 day) cocaine self-administration; the membrane excitability was increased in LTB neurons but decreased in RS neurons. These short-term exposure-induced effects were transient as they were present on withdrawal day 1 but disappeared on withdrawal day 21. However, extended exposure (21 day) led to sustained increase in the membrane excitability of LTB neurons such that it lasted over 21 days into the withdrawal period. These results suggest that CeA neurons can be a cellular target for cocaine to reshape the circuitry mediating negative affects during withdrawal, and that the long-lasting cellular alterations in selective subpopulations of CeA neurons may lead to unbalanced CeA processing, thus contributing to the progressive aggravation of negative affective states during withdrawal from chronic cocaine exposure.
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http://dx.doi.org/10.1038/npp.2013.124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773674PMC
October 2013

Sleep: a synchrony of cell activity-driven small network states.

Eur J Neurosci 2013 Jul 8;38(2):2199-209. Epub 2013 May 8.

Sleep and Performance Research Center, Washington State University, Pullman, WA, USA.

We posit a bottom-up sleep-regulatory paradigm in which state changes are initiated within small networks as a consequence of local cell activity. Bottom-up regulatory mechanisms are prevalent throughout nature, occurring in vastly different systems and levels of organization. Synchronization of state without top-down regulation is a fundamental property of large collections of small semi-autonomous entities. We posit that such synchronization mechanisms are sufficient and necessary for whole-organism sleep onset. Within the brain we posit that small networks of highly interconnected neurons and glia, for example cortical columns, are semi-autonomous units oscillating between sleep-like and wake-like states. We review evidence showing that cells, small networks and regional areas of the brain share sleep-like properties with whole-animal sleep. A testable hypothesis focused on how sleep is initiated within local networks is presented. We posit that the release of cell activity-dependent molecules, such as ATP and nitric oxide, into the extracellular space initiates state changes within the local networks where they are produced. We review mechanisms of ATP induction of sleep-regulatory substances and their actions on receptor trafficking. Finally, we provide an example of how such local metabolic and state changes provide mechanistic explanations for clinical conditions, such as insomnia.
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http://dx.doi.org/10.1111/ejn.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713192PMC
July 2013

Dopamine triggers heterosynaptic plasticity.

J Neurosci 2013 Apr;33(16):6759-65

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

As a classic neuromodulator, dopamine has long been thought to modulate, rather than trigger, synaptic plasticity. In contrast, our present results demonstrate that within the parallel projections of dopaminergic and GABAergic terminals from the ventral tegmental area to the nucleus accumbens core (NAcCo), action-potential-activated release of dopamine heterosynaptically triggers LTD at GABAergic synapses, which is likely mediated by activating presynaptically located dopamine D1 class receptors and expressed by inhibiting presynaptic release of GABA. Moreover, this dopamine-mediated heterosynaptic LTD is abolished after withdrawal from cocaine exposure. These results suggest that action-potential-dependent dopamine release triggers very different cellular consequences from those induced by volume release or pharmacological manipulation. Activation of the ventral tegmental area to NAcCo projections is essential for emotional and motivational responses. This dopamine-mediated LTD allows a flexible output of NAcCo neurons, whereas disruption of this LTD may contribute to the rigid emotional and motivational state observed in addicts during cocaine withdrawal.
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http://dx.doi.org/10.1523/JNEUROSCI.4694-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664188PMC
April 2013