Nucleus Accumbens Lateral Shell Research Articles

Activation of Kv7 channels normalizes hyperactivity of the VTA-NAcLat circuit and attenuates methamphetamine-induced conditioned place preference and sensitization in mice.

The brain circuit projecting from the ventral tegmental area (VTA) to the nucleus accumbens lateral shell (NAcLat) has a key role in methamphetamine (MA) addiction. As different dopamine (DA) neuron subpopulations in the VTA participate in different neuronal circuits, it is a challenge to isolate these DA neuron subtypes. Using retrograde tracing and Patch-seq, we isolated DA neurons in the VTA-NAcLat circuit in MA-treated mice and performed gene expression profiling. Among the differentially expressed genes, KCNQ genes were dramatically downregulated. KCNQ genes encode Kv7 channel proteins, which modulate neuronal excitability. Injection of both the Kv7.2/3 agonist ICA069673 and the Kv7.4 agonist fasudil into the VTA attenuated MA-induced conditioned place preference and locomotor sensitization and decreased neuronal excitability. Increasing Kv7.2/3 activity decreased neural oscillations, synaptic plasticity and DA release in the VTA-NacLat circuit in MA-treated mice. Furthermore, overexpression of only Kv7.3 channels in the VTA-NacLat circuit was sufficient to attenuate MA-induced reward behavior and decrease VTA neuron excitability. Activation of Kv7 channels in the VTA may become a novel treatment strategy for MA abuse.

Distinct Roles of Dopamine Receptor Subtypes in the Nucleus Accumbens during Itch Signal Processing.

Ventral tegmental area (VTA) dopaminergic neurons, which are well known for their central roles in reward and motivation-related behaviors, have been shown to participate in itch processing via their projection to the nucleus accumbens (NAc). However, the functional roles of different dopamine receptor subtypes in subregions of the NAc during itch processing remain unknown. With pharmacological approaches, we found that the blockade of dopamine D1 receptors (D1R), but not dopamine D2 receptors (D2R), in the lateral shell (LaSh) of the NAc impaired pruritogen-induced scratching behavior in male mice. In contrast, pharmacological activation of D2R in both the LaSh and medial shell (MeSh) of the NAc attenuated the scratching behavior induced by pruritogens. Consistently, we found that dopamine release, as detected by a dopamine sensor, was elevated in the LaSh rather than the MeSh of the NAc at the onset of scratching behavior. Furthermore, the elevation of dopamine release in the LaSh of the NAc persisted even though itch-relieving behavior was blocked, suggesting that the dopamine signal in the NAc LaSh represents a motivational component of itch processing. Our study revealed different dynamics of dopamine release that target neurons expressing two dopamine receptors subtypes within different subregions of the NAc, and emphasized that D1R in the LaSh of the NAc is important in itch signal processing.SIGNIFICANCE STATEMENT Dopamine has been implicated in itch signal processing. However, the mechanism underlying the functional role of dopamine in itch processing remains largely unknown. Here, we examined the role of dopamine D1 receptor (D1R) and D2R in the nucleus accumbens (NAc) shell during pruritogen-induced scratching behavior. We demonstrated that D1R in the NAc lateral shell (LaSh) play an important role in motivating itch-induced scratching behavior, while activation of D2R would terminate scratching behavior. Our study revealed the diverse functional roles of dopamine signals in the NAc shell during itch processing.

Behavioral Engagement With Playable Objects Resolves Stress-Induced Adaptive Changes by Reshaping the Reward System

BackgroundThe reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood. MethodsMice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects. ResultsHere, we show that repeated restraint induces dopamine surges into the nucleus accumbens–lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D1 receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress–induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area–to–NAc-lSh and NAc-lSh–to–ventral pallidum circuits. ConclusionsThese results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.

Plastic changes in amygdala subregions by voluntary running contribute to exercise-induced hypoalgesia in neuropathic pain model mice.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic pain, but exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. Since a growing body of evidence implicated the amygdala (Amyg) as a critical node in emotional affective aspects of chronic pain, we hypothesized that the Amyg may play important roles to produce EIH effects. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of voluntary running (VR) on the basal amygdala (BA) and the central nuclei of amygdala (CeA). The present study indicated that VR significantly improved heat hyperalgesia which was exacerbated in PSL-Sedentary mice, and that a significant positive correlation was detected between total running distances after PSL-surgery and thermal withdrawal latency. The number of activated glutamate (Glu) neurons in the medal BA (medBA) was significantly increased in PSL-Runner mice, while those were increased in the lateral BA in sedentary mice. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, but these numbers were significantly decreased in PSL-Runner mice. In addition, a tracer experiment demonstrated a marked increase in activated Glu neurons in the medBA projecting into the nucleus accumbens lateral shell in runner mice. Thus, our results suggest that VR may not only produce suppression of the negative emotion such as fear and anxiety closely related with pain chronification, but also promote pleasant emotion and hypoalgesia. Therefore, we conclude that EIH effects may be produced, at least in part, via such plastic changes in the Amyg.

Circuit directionality for motivation: Lateral accumbens-pallidum, but not pallidum-accumbens, connections regulate motivational attraction to reward cues.

Sign-tracking behavior, in which animals interact with a cue that predicts reward, provides an example of how incentive salience can be attributed to cues and elicit motivation. The nucleus accumbens (NAc) and ventral pallidum (VP) are two regions involved in cue-driven motivation. The VP, and NAc subregions including the medial shell and core, are critical for sign-tracking. Further, connections between the medial shell and VP are known to participate in sign-tracking and other motivated behaviors. The NAc lateral shell (NAcLSh) is a distinct and understudied subdivision of the NAc, and its contribution to the process by which reward cues acquire value remains unclear. The NAcLSh has been implicated in reward-directed behavior, and has reciprocal connections with the VP, suggesting that NAcLSh and VP interactions could be important mechanisms for incentive salience. Here, we use DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and an intersectional viral delivery strategy to produce a biased inhibition of NAcLSh neurons projecting to the VP, and vice versa. We find that disruption of connections from NAcLSh to VP reduces sign-tracking behavior while not affecting consumption of food rewards. In contrast, VP to NAcLSh disruption affected neither sign-tracking nor reward consumption, but did produce a greater shift in animals' behavior more towards the reward source when it was available. These findings indicate that the NAcLSh → VP pathway plays an important role in guiding animals towards reward cues, while VP → NAcLSh back-projections may not and may instead bias motivated behavior towards rewards.

A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System

Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and negative motivational stimuli is incompletely understood. Using invivo fiber photometry, we simultaneously recorded activity in DA terminals in different nucleus accumbens (NAc) subnuclei during an aversive and reward conditioning task. We find that DA terminals in the ventral NAc medial shell (vNAcMed) are excited by unexpected aversive outcomes and to cues that predict them, whereas DA terminals in other NAc subregions are persistently depressed. Excitation to reward-predictive cues dominated in the NAc lateral shell and was largely absent in the vNAcMed. Moreover, we demonstrate that glutamatergic (VGLUT2-expressing) neurons in the lateral hypothalamus represent a key afferent input for providing information about aversive outcomes to vNAcMed-projecting DA neurons. Collectively, we reveal the distinct functional contributions of separate mesolimbic DA subsystems and their afferent pathways underlying motivated behaviors. VIDEO ABSTRACT.

Nucleus Accumbens Subnuclei Regulate Motivated Behavior via Direct Inhibition and Disinhibition of VTA Dopamine Subpopulations

Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent inputs, little is known about the circuits in which they are embedded. Using retrograde tracing, electrophysiology, optogenetics, and behavioral assays, we identify principles of afferent-specific control in the mesolimbic DA system. Neurons in the medial shell subdivision of the nucleus accumbens (NAc) exert direct inhibitory control over two separate populations of mesolimbic DA neurons by activating different GABA receptor subtypes. In contrast, NAc lateral shell neurons mainly synapse onto ventral tegmental area (VTA) GABA neurons, resulting in disinhibition of DA neurons that project back to the NAc lateral shell. Lastly, we establish a critical role for NAc subregion-specific input to the VTA underlying motivated behavior. Collectively, our results suggest a distinction in the incorporation of inhibitory inputs between different subtypes of mesolimbic DA neurons.

Projection-Target-Defined Effects of Orexin and Dynorphin on VTA Dopamine Neurons

Circuit-specific signaling of ventral tegmental area (VTA) dopamine neurons drives different aspects of motivated behavior, but the neuromodulatory control of these circuits is unclear. We tested the actions of co-expressed lateral hypothalamic peptides, orexin A (oxA) and dynorphin (dyn), on projection-target-defined dopamine neurons in mice. We determined that VTA dopamine neurons that project to the nucleus accumbens lateral shell (lAcbSh), medial shell (mAcbSh), and basolateral amygdala (BLA) arelargely non-overlapping cell populations with different electrophysiological properties. Moreover, the neuromodulatory effects of oxA and dyn on these three projections differed. OxA selectively increased firing in lAcbSh- and mAcbSh-projecting dopamine neurons. Dyn decreased firing in the majority of mAcbSh- and BLA-projecting dopamine neurons but reduced firing only in a small fraction of those that project to the lAcbSh. In conclusion, the oxA-dyn input to the VTA may drive reward-seeking behavior by tuning dopaminergic output in a projection-target-dependent manner.

Input-specific control of reward and aversion in the ventral tegmental area

Ventral tegmental area (VTA) dopamine neurons play important roles in adaptive and pathological brain functions related to reward and motivation. It is unknown, however, if subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures and whether inputs to the VTA differentially modulate such circuits. Here we show that because of differences in synaptic connectivity activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to nucleus accumbens lateral shell while lateral habenula neurons synapse primarily on dopamine neurons projecting to medial prefrontal cortex as well as on GABAergic neurons in the VTA tail. These results establish that distinct VTA circuits generate reward and aversion and thereby provide a novel framework for understanding the circuit basis of adaptive and pathological motivated behaviors.

Projection-Specific Modulation of Dopamine Neuron Synapses by Aversive and Rewarding Stimuli

Midbrain dopamine (DA) neurons are not homogeneous but differ in their molecular properties and responses to external stimuli. We examined whether the modulation of excitatory synapses on DA neurons by rewarding or aversive stimuli depends on the brain area to which these DA neurons project. We identified DA neuron subpopulations in slices after injection of "Retrobeads" into single target areas of adult mice and found differences in basal synaptic properties. Administration of cocaine selectively modified excitatory synapses on DA cells projecting to nucleus accumbens (NAc) medial shell while an aversive stimulus selectively modified synapses on DA cells projecting to medial prefrontal cortex. In contrast, synapses on DA neurons projecting to NAc lateral shell were modified by both rewarding and aversive stimuli, which presumably reflects saliency. These results suggest that the mesocorticolimbic DA system may be comprised of three anatomically distinct circuits, each modified by distinct aspects of motivationally relevant stimuli.

Decreased choline acetyltransferase immunoreactivity in discrete striatal subregions following chronic haloperidol in rats.

Neuronal loss within the basal ganglia has been hypothesized to play a role in movement disorders (e.g., tardive dyskinesia) that often occur following chronic neuroleptic treatment. Previous studies in animal models have provided some support to this possibility, but have not assessed regionally specific changes after chronic neuroleptic administration. The present study examined whether counts of neurons containing acetylcholine, described as large aspiny type II neurons, were altered in subregions of the corpus striatum and nucleus accumbens following chronic haloperidol administration in rats. Rats were administered haloperidol decanoate (21 mg/kg, i.m.) or vehicle every third week for 24 weeks. Following 4 weeks of withdrawal from the drug, predefined regions were examined for choline acetyltransferase (ChAT) immunoreactive (ir) cells. Compared to the vehicle group, the haloperidol group showed significant reductions in ChAT-ir cell counts in the ventrolateral striatum, nucleus accumbens core, and nucleus accumbens lateral shell. No significant differences were found in the other regions examined: dorsolateral striatum, dorsomedial striatum, ventromedial striatum, nucleus accumbens medial shell, and horizontal limb of the diagonal band. These findings indicate that there may be regionally specific alterations in ChAT-ir cells following chronic haloperidol treatment, supporting previous hypotheses of striatal cholinergic cell loss resulting from chronic neuroleptic treatment. More importantly, the regions affected (ventrolateral striatum and nucleus accumbens) are critical in the regulation of oral movements, thus suggesting that alterations in cholinergic cell activity, and perhaps actual loss of cholinergic cells in these regions, may be important in the manifestation of late-onset oral dyskinesia.