BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens.
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ABSTRACT:
SUBMITTER: White AO
PROVIDER: S-EPMC4894971 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The aim of the present study is to investigate whether cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc) is causally linked. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of long-term synaptic plasticity, learning, and drug addiction. We examined whether blocking CaMKII activity in the VTA affected cocaine conditioned place preference (CPP) and cocaine-evoked synaptic plasticity in its target brain region, the NAc. TatCN21 is a CaMKII inhibitory peptide that blocks both stimulated and autonomous CaMKII activity with high selectivity. We report that intra-VTA microinjections of tatCN21 before cocaine conditioning blocked the acquisition of cocaine CPP, whereas intra-VTA microinjections of tatCN21 before saline conditioning did not significantly affect cocaine CPP, suggesting that the CaMKII inhibitor blocks cocaine CPP through selective disruption of cocaine-cue-associated learning. Intra-VTA tatCN21 before cocaine conditioning blocked cocaine-evoked depression of excitatory synaptic transmission in the shell of the NAc slices ex vivo. In contrast, intra-VTA microinjection of tatCN21 just before the CPP test did not affect the expression of cocaine CPP and cocaine-induced synaptic plasticity in the NAc shell. These results suggest that CaMKII activity in the VTA governs cocaine-evoked synaptic plasticity in the NAc during the time window of cocaine conditioning.
| S-EPMC3924533 | biostudies-literature
Project description:We examine synaptic connectivity and cocaine-evoked plasticity at specific networks within the nucleus accumbens (NAc). We identify distinct subpopulations of D1+ medium spiny neurons (MSNs) that project to either the ventral pallidum (D1+VP) or the ventral tegmental area (D1+VTA). We show that inputs from the ventral hippocampus (vHPC), but not the basolateral amygdala (BLA), are initially biased onto D1+VTA MSNs. However, repeated cocaine exposure eliminates the bias of vHPC inputs onto D1+VTA MSNs, while strengthening BLA inputs onto D1+VP MSNs. Our results reveal that connectivity and plasticity depend on the specific inputs and outputs of D1+ MSNs and highlight the complexity of cocaine-evoked circuit level adaptations in the NAc.
| S-EPMC6733522 | biostudies-literature
Project description:Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brain-derived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD.
| S-EPMC2660722 | biostudies-literature
Project description:Cocaine use and abstinence induce long-term synaptic alterations in the excitatory input to nucleus accumbens (NAc) medium spiny neurons (MSNs). The NAc regulates reward-related behaviors through two parallel projections to the ventral pallidum (VP)-originating in D1 or D2-expressing MSNs (D1-MSNs→VP; D2-MSNs→VP). The activity of these projections depends on their excitatory synaptic inputs, but it is not known whether and how abstinence from cocaine affects the excitatory transmission to D1-MSNs→VP and D2-MSNs→VP. Here we examined different forms of cocaine-induced synaptic plasticity in the inputs from the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) to NAc D1-MSNs→VP and putative D2-MSNs→VP (pD2-MSNs→VP) in the core and shell subcompartments of the NAc. We used the whole-cell patch-clamp technique to record excitatory postsynaptic currents from D1-tdTomato mice injected with ChR2 in either the BLA or the mPFC and retrograde tracer (RetroBeads) in the VP. We found that cocaine conditioned place preference (CPP) followed by abstinence potentiated the excitatory input from the BLA and mPFC to both D1-MSNs→VP and pD2-MSNs→VP. Interestingly, while the strengthening of the inputs to D1-MSNs→VP was of postsynaptic origin and manifested as increased AMPA to NMDA ratio, in pD2-MSNs→VP plasticity was predominantly presynaptic and was detected as changes in the paired-pulse ratio and coefficient of variation. Lastly, some of the changes were sex-specific. Overall our data show that abstinence from cocaine changes the excitatory inputs to both D1-MSNs→VP and pD2-MSNs→VP but with different mechanisms. This may help understand how circuits converging into the VP change after cocaine exposure.
| S-EPMC9205871 | biostudies-literature
Project description:Recent exome sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several human intellectual disabilities and cognitive disorders. However, it is currently unknown how mutations in BAF complexes result in impaired cognitive function. Postmitotic neurons express a neuron-specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Mice harboring selective genetic manipulations of BAF53b have severe defects in long-term memory and long-lasting forms of hippocampal synaptic plasticity. We rescued memory impairments in BAF53b mutant mice by reintroducing BAF53b in the adult hippocampus, which suggests a role for BAF53b beyond neuronal development. The defects in BAF53b mutant mice appeared to derive from alterations in gene expression that produce abnormal postsynaptic components, such as spine structure and function, and ultimately lead to deficits in synaptic plasticity. Our results provide new insight into the role of dominant mutations in subunits of BAF complexes in human intellectual and cognitive disorders.
| S-EPMC3777648 | biostudies-literature
Project description:Addictive drug use causes long-lasting changes in synaptic strength and dendritic spine morphology in the nucleus accumbens that might underlie the vulnerability to relapse. Although activity in mesocorticolimbic circuitry is required for reinstating cocaine seeking, its role in reinstatement-associated synaptic plasticity is not well characterized. Using rats extinguished from cocaine self-administration, we found potentiated synaptic strength (assessed as the AMPA/NMDA current amplitude ratio) and increased spine head diameter in medium spiny neurons in the accumbens core (NAcore). The basal changes in synaptic strength and morphology in cocaine-extinguished animals were further augmented during cocaine-induced reinstatement. Two NAcore afferents contributing to cocaine reinstatement are glutamatergic inputs from the prelimbic prefrontal cortex (PL) and dopamine from the ventral tegmental area (VTA). Pharmacological inhibition of either PL or VTA prevented cocaine-primed reinstatement. However, inhibiting the PL further potentiated AMPA/NMDA and spine head diameter, while inactivating the VTA or the combined systemic administration of dopamine D1 and D2 antagonists prevented the increase in AMPA/NMDA and spine diameter induced by cocaine priming. These data indicate that neuronal activity in the VTA and associated dopamine receptor stimulation is necessary for the synaptic potentiation in the NAcore during cocaine-induced reinstatement. Although activity in the PL was necessary for reinstatement, it inhibited synaptic potentiation initiated by an acute cocaine injection. Thus, although the PL and VTA differentially regulate the direction of synaptic plasticity induced by a cocaine-priming injection, coordinated synaptic potentiation by both NAcore afferents is necessary for cocaine-induced relapse.
| S-EPMC3957111 | biostudies-other
Project description:Cocaine exposure induces plasticity of glutamatergic synapses of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), which has been proposed to contribute to its addictive behavior. The mechanisms underlying cocaine-induced plasticity are not fully understood. The orphan glutamate delta-1 (GluD1) receptor is a member of the ionotropic glutamate receptor family but does not function as a typical ligand-gated ion channel. Instead it serves a synaptogenic function by interacting with presynaptic Neurexin protein. Recent neuroanatomical studies have demonstrated enriched expression of GluD1 in the NAc but its role in reward behavior, MSN function, and drug-induced plasticity remains unknown. Using a combination of constitutive and conditional GluD1 KO models, we evaluated the effect of GluD1 ablation on cocaine-conditioned place preference (CPP) and cocaine-induced structural and functional plasticity. GluD1 KO mice showed higher cocaine CPP. Selective ablation of GluD1 from striatal neurons but not cortico-limbic excitatory neurons reproduced higher CPP. Higher cocaine preference in GluD1 KO correlated with an increase in spine density, greater maturation of dendritic spines, and basally upregulated spine-regulating active cofilin. GluD1 loss did not affect basal excitatory neurotransmission or plasticity but masked the generation of cocaine-induced silent synapses. Finally, loss of GluD1 increased the GluN2B subunit contribution to NMDA receptor currents in MSNs and a partial agonist of GluN2B-containing NMDA receptors normalized the higher active cofilin and cocaine preference in GluD1 KO mice. Together, these findings demonstrate a critical role of GluD1 in controlling susceptibility to cocaine preference and cocaine-induced plasticity by modulating NMDA receptor subunit contribution.
| S-EPMC6185950 | biostudies-literature
Project description:Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.
| S-EPMC3565539 | biostudies-literature
Project description:RATIONALE:Environmental stimuli, or cues, associated with the use of drugs such as cocaine are one of the primary drivers of relapse. Thus, identifying mechanisms to reduce the motivational properties of drug cues is an important research goal. OBJECTIVES:The purpose of this study was to identify cellular signaling events in the nucleus accumbens (NAc) that are induced when a cocaine cue memory is either extinguished through repeated cue presentation in the absence of drug, or when the memory is reactivated and reconsolidated by a brief cue re-exposure. Signaling events specific to extinction or reconsolidation represent potential targets for pharmacotherapeutics that may enhance extinction or disrupt reconsolidation to reduce the likelihood of relapse. METHODS:Male Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. Following a period of self-administration, the memory for the cocaine-associated cue was either extinguished, reactivated, or not manipulated (control) 15 min before sacrifice. Tissue from the NAc was subsequently analyzed using mass spectrometry based phosphoproteomics to identify cellular signaling events induced by each condition. RESULTS:Extinction and reconsolidation of the cocaine cue memory produced both common and distinct changes in protein phosphorylation. Notably, there were no significant changes in protein phosphorylation that were modulated in the opposite direction by the two behavioral conditions. Comparison of NAc phosphoproteomic changes to previously identified changes in the basolateral amygdala (BLA) revealed that cue extinction increases phosphorylation at serine (S) 883 of the GABAB receptor subunit 2 and on S14 of syntaxin 1a in both regions, while no common regional signaling events were identified in the reconsolidation group. CONCLUSIONS:Phosphoproteomics is a useful tool for identifying signaling cascades involved in different memory processes and revealed novel potential targets for selectively targeting extinction versus reconsolidation of a cocaine cue memory. Furthermore, cross region analysis suggests that cue extinction may produce unique signaling events associated with increased inhibitory signaling.
| S-EPMC6374162 | biostudies-literature
Project description:Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3? (GSK3?) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3? activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3? in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3? in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3?. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+ currents, as a potential downstream target of GSK3?. We found increased levels of active GSK3? and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3? knockdown. Furthermore, knockdown of GSK3? in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3?-dependent tLTP changes in CUMS mice. Our results identify GSK3? regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3?-Kv4.2 axis may be an attractive therapeutic target for MDD.
| S-EPMC7149226 | biostudies-literature