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Complex circuit interactions within the nucleus accumbens (NAc) facilitate goal-directed behavior. Medium spiny neurons (MSNs) mediate NAc output by projecting to functionally divergent brain regions, a property conferred, in part, by the differential projection patterns of D1- and D2 dopamine receptor-expressing MSNs. Glutamatergic afferents to the NAc direct MSN output by recruiting feedforward inhibitory microcircuits comprised of parvalbumin (PV)-expressing interneurons (INs). Furthermore, the GABA heteroreceptor (GABAR), a G-coupled G-protein-coupled receptor, is expressed at glutamatergic synapses throughout the mesolimbic network, yet its physiological context and synaptic mechanism within the NAc remains unknown. Here, we explored GABAR function at glutamatergic synapses within PV-IN-embedded microcircuits in the NAc core of male mice. We found that GABAR is expressed presynaptically and recruits a noncanonical signaling mechanism to reduce glutamatergic synaptic efficacy at D1(+) and D1(-) (putative D2) MSN subtypes. Furthermore, PV-INs, a robust source of neuronal GABA in the NAc, heterosynaptically target GABAR to selectively modulate glutamatergic transmission onto D1(+) MSNs. These findings elucidate a new mechanism of feedforward inhibition and refine mechanisms by which GABA heteroreceptors modulate mesolimbic circuit function. Glutamatergic transmission in the nucleus accumbens (NAc) critically contributes to goal-directed behaviors. However, intrinsic microcircuit mechanisms governing the integration of these synapses remain largely unknown. Here, we show that parvalbumin-expressing interneurons within feedforward microcircuits heterosynaptically target GABA heteroreceptors (GABAR) on glutamate terminals. Activation of presynaptically-expressed GABAR decreases glutamatergic synaptic strength by engaging a non-canonical signaling pathway that interferes with vesicular exocytotic release machinery. These findings offer mechanistic insight into the role of GABA heteroreceptors within reward circuitry, elucidate a novel arm to feedforward inhibitory networks, and inform the growing use of GABAR-selective pharmacotherapy for various motivational disorders, including addiction, major depressive disorder, and autism (Cousins et al., 2002; Kahn et al., 2009; Jacobson et al., 2018; Stoppel et al., 2018; Pisansky et al., 2019).
Copyright © 2019 the authors.
The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine. Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation. These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.
Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.
Glutamatergic transmission in the nucleus accumbens shell (NAcSh) is a substrate for reward learning and motivation. Metabotropic glutamate (mGlu) receptors regulate NAcSh synaptic strength by inducing long-term depression (LTD). Inputs from prefrontal cortex (PFC) and medio-dorsal thalamus (MDT) drive opposing motivated behaviors yet mGlu receptor regulation of these synapses is unexplored. We examined Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific populations of NAc medium spiny neurons (MSNs) using D1tdTom BAC transgenic mice and optogenetics. Synaptically evoked long-term depression (LTD) at MDT-NAcSh synapses required mGlu but not mGlu and was specific for D1(+) MSNs, whereas PFC LTD was expressed at both D1(+) and D1(-) MSNs and required mGlu but not mGlu. Two weeks after five daily non-contingent cocaine exposures (15 mg/kg), LTD was attenuated at MDT-D1(+) synapses but was rescued by the mGlu5-positive allosteric modulator (PAM) VU0409551. These results highlight unique plasticity mechanisms regulating specific NAcSh synapses.
Dopamine signaling encodes reward learning and motivated behavior through modulation of synaptic signaling in the nucleus accumbens, and aberrations in these processes are thought to underlie obsessive behaviors associated with alcohol abuse. The nucleus accumbens is divided into core and shell sub-regions with overlapping but also divergent contributions to behavior. Here we optogenetically targeted dopamine projections to the accumbens allowing us to isolate stimulation of dopamine terminals ex vivo. We applied 5 pulse (phasic) light stimulations to probe intrinsic differences in dopamine release parameters across regions. Also, we exposed animals to 4weeks of chronic intermittent ethanol vapor and measured phasic release. We found that initial release probability, uptake rate and autoreceptor inhibition were greater in the accumbens core compared to the shell, yet the shell showed greater phasic release ratios. Following chronic ethanol, uptake rates were increased in the core but not the shell, suggesting region-specific neuronal adaptations. Conversely, kappa opioid receptor function was upregulated in both regions to a similar extent, suggesting a local mechanism of kappa opioid receptor regulation that is generalized across the nucleus accumbens. These data suggest that dopamine axons in the nucleus accumbens core and shell display differences in intrinsic release parameters, and that ethanol-induced adaptations to dopamine neuron terminal fields may not be homogeneous. Also, chronic ethanol exposure induces an upregulation in kappa opioid receptor function, providing a mechanism for potential over-inhibition of accumbens dopamine signaling which may negatively impact downstream synaptic function and ultimately bias choice towards previously reinforced alcohol use behaviors.
Copyright © 2017 Elsevier Inc. All rights reserved.
Dopaminergic signaling differences in the nucleus accumbens (NAcc) seemingly predispose rats to adopt different physical activity behaviors. Physical activity behavior also may be regulated through peripheral mechanisms (i.e., muscle and fat derived as well as hormonal signals). We hypothesize that physical activity behavior is regulated by the convergence of central and peripheral mechanisms onto the NAcc.
The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake.
Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation.
© 2015 International Society for Neurochemistry.
Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies.
Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519-11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long-projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models.
Copyright © 2015 the American Physiological Society.