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Figure supplement 1. Delineation of ventral midbrain DA neuron groups. DOI: https://doi.org/10.7554/eLife.39786.018
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Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral s...
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Diseases of the motor-conducting system that cause moving disability affect socio-economic activity as well as human dignity. Neurolathyrism, konzo, and amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) have attracted researchers to study the pathology of motor neuron (MN) diseases such as ALS. I have been studying neurolathyris...
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... ; the expression of Cre and the absence of Flp (AAV8-nEF-Con/Foff-GCaMP6m) (Root et al., 2020). To target VGluT2+/TH+ neurons (glutamate dopamine neurons), VGluT2::Cre/TH::Flp mice were injected in VTA with AAVs encoding GCaMP6m dependent on the expression of Cre and Flp (AAV8-nEF-Con/Fon-GCaMP6m) (Chuhma et al., 2018;Poulin et al., 2018;Mingote et al., 2019;Buck et al., 2023). All mice were implanted with optic fibers dorsal to VTA and foodrestricted to promote consumption of reward ( Figure 1). ...
Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of VTA VGluT2+ neurons are capable of co-transmitting glutamate and GABA (VGluT2+VGaT+ neurons), transmitting glutamate without GABA (VGluT2+VGaT- neurons), or co-transmitting glutamate and dopamine (VGluT2+TH+ neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified that neuronal activity of each VGluT2+ subpopulation is sensitive to reward value but signaled this in different ways. The phasic maximum activity of VGluT2+VGaT+ neurons increased with sucrose concentration, whereas VGluT2+VGaT- neurons increased maximum and sustained activity with sucrose concentration, and VGluT2+TH+ neurons increased sustained but not maximum activity with sucrose concentration. Additionally, VGluT2+ subpopulations signaled consummatory preferences in different ways. VGluT2+VGaT- neurons and VGluT2+TH+ neurons showed a signaling preference for a behaviorally-preferred fat reward over sucrose, but in temporally-distinct ways. In contrast, VGluT2+VGaT+ neurons uniquely signaled a less behaviorally-preferred sucrose reward compared with fat. Further experiments suggested that VGluT2+VGaT+ consummatory reward-related activity was related to sweetness, partially modulated by hunger state, and not dependent on caloric content or behavioral preference. All VGluT2+ subtypes increased neuronal activity following aversive stimuli but VGluT2+VGaT+ neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2+VGaT+ neurons during low intensity footshock enhanced fear-related behavior without inducing place preference or aversion. We interpret these data such that VTA glutamatergic subpopulations signal different elements of rewarding and aversive experiences and highlight the unique role of VTA VGluT2+VGaT+ neurons in enhancing the salience of behavioral experiences.
... This has been interpreted as a "permissive" role for DA (Schulz & Reynolds, 2013) -that is, DA simply needs to be present -but it has also been argued that cue-evoked DA release drives the CIN pauses (Chuhma et al., 2014;Straub, et al., 2014). In dorsal striatal brain slices, CIN pauses can be produced by local electrical stimulation (Kharkwal at al., 2016), or by stimulation of incoming thalamic axons (Ding et al., 2010) or nigral DA axons (Straub et al., 2014;Chuhma et al., 2018;Cai & Ford, 2018). These artificially evoked CIN pauses are dependent on DA, and D2 receptors on CINs (Kharkwal et al., 2016). ...
... ; https://doi.org/10.1101/2024.05.09.593336 doi: bioRxiv preprint begun. Cue-evoked DA, and co-released glutamate, is thus more likely to contribute to shaping CIN activity during the subsequent "rebound" phase (Wieland et al., 2014;Chuhma et al., 2018). Even at that later time, the impact on CIN firing is likely to be modulatory rather than a strong glutamatedriven excitation, since the DA Go response is time-locked to cues while the CIN rebound is instead movement-related. ...
Movement, motivation and reward-related learning depend strongly on striatal dopamine and acetylcholine. These neuromodulators each regulate the other, and disturbances to their coordinated signals contribute to human disorders ranging from Parkinson’s Disease to depression and addiction. Pauses in the firing of cholinergic interneurons (CINs) are thought to coincide with pulses in dopamine release that encode reward prediction errors (RPEs), together shaping synaptic plasticity and thereby learning. However, such models are based upon recordings from unidentified neurons, and do not incorporate the distinct characteristics of striatal subregions. Here we compare the firing of identified, individual CINs to dopamine release as unrestrained rats performed a probabilistic decision-making task. The relationships between CIN spiking, dopamine release, and behavior varied strongly by subregion. In dorsal-lateral striatum a Go! cue evoked burst-pause CIN spiking, quickly followed by a very brief (~150ms) dopamine pulse that was unrelated to RPE. In dorsal-medial striatum the same cue evoked only a CIN pause; this pause was curtailed by a movement-selective rebound in firing. Finally in ventral striatum a reward cue evoked slower, RPE-coding increases in both dopamine and CIN firing, without any distinct pause. Our results demonstrate a spatial and temporal dissociation between CIN pauses and dopamine RPE signals, and will inform new models of striatal microcircuits and their contributions to behavior.
... Striatal DA axons also release glutamate, 40,69-75 albeit primarily from distinct vesicles 76 in different varicosities and axonal branches 77,78 and with regional 72 as well as subregional 79,80 heterogeneity. Key targets for co-released glutamate in lateral dStr and NAc are ChIs. ...
... Key targets for co-released glutamate in lateral dStr and NAc are ChIs. [79][80][81][82][83] Given that ChIs directly trigger DA release by activating nAChRs on DA axons, 13,14,16 a potential factor in our experiments using phasic optical stimulation of DA axons is that co-released glutamate might drive ChIs to activate DA axons and the co-release of DA plus GABA. 36 This would provide an additional catalyst for GABA autoregulation of DA release. ...
... In lateral dStr, phasic optical stimulation of DA axons induces a short pause of firing in ChIs, followed by a delayed burst of activity mediated by activation of group 1 metabotropic glutamate receptors (mGluR1s) by co-released glutamate. 79,80 We tested a possible role for this dStr microcircuit by applying PTX in the presence of an mGluR1 antagonist, JNJ-16259685 (10 μM). 80 PTX enhanced 1 p and 10 p optically evoked [DA] o in the dStr in the presence of the antagonist, with the usual greater amplification of 10 p versus 1 p (p = 0.0121, paired t test, n = 6 mice) indicating a lack of involvement of mGluR1 on DA-release regulation by co-released GABA ( Figure 6A). ...
Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.
... These studies suggested that the TAN pause may be closely related to reward-related learning in BG. More interestingly, many empirical studies have shown that TAN and DA are tightly coupled in a reciprocal fashion during reward-based motor tasks (Cragg 2006;Morris et al. 2004;Threlfell et al. 2012;Cachope et al. 2012;Chuhma et al. 2018). For example, Morris et al. have shown that the TAN pause activity and DA release are time-locked when receiving the same reward-based task (Morris et al. 2004). ...
... For example, Morris et al. have shown that the TAN pause activity and DA release are time-locked when receiving the same reward-based task (Morris et al. 2004). Threlfell et al. suggested that the DA release can be triggered by synchronized pause activity in TAN (Threlfell et al. 2012), and the phasic DA release regulates the duration of TAN pause (Chuhma et al. 2018). Hence, the dynamic interplay between TAN pause and DA release in the striatum is important in reward-related selection behaviors. ...
... This result also confirms some empirical findings that DA can modulate the duration of the TAN pause. (Deng et al. 2007;Chuhma et al. 2018). ...
The basal ganglia (BG) plays a key role in action selection. Physiological experiments have suggested that the reciprocal interaction between tonically active neurons (TANs) and dopamine (DA) is closely related to reward-based behaviors. However, the functional role of TAN-DA interaction in action selection remains unclear. In this study, a cortico-BG model including TAN-DA interaction mechanism is developed to explore the action selection mechanism of BG. The results show that in the default case, direct, indirect, and hyperdirect pathways are responsible for promoting, suppressing, and stopping the formation of stimulus-action associations, respectively. In the case of reinforcement learning, a single rewarded action is selected according to the combination of the TAN-DA dependent reinforcement mechanism and Hebbian mechanism with a gradual transfer from the former to the latter. Besides, a longer exploratory phase occurs when switching the reward to a new action because additional trials are required to overcome the habituation previously induced by the Hebbian mechanism. In the Parkinsonian state, the reinforcement mechanism is disrupted, and the resting tremor occurs due to dopamine deficiency. Although the model’s performance significantly improves due to the levodopa treatment, it is still inferior to the healthy state. This phenomenon is consistent with the experimental results and is explained theoretically via the TAN pause duration and phasic DA release. Furthermore, the model’s performances in multi-action selection further verify the rationality of the TAN-DA-dependent reinforcement mechanism. Our work provides a more complete framework for studying the action selection mechanism of basal ganglia.
... The release of DA in the striatum impacts on dMSNs and iMSNs activity via the activation of D1 or D2 receptors, respectively [32][33][34][35][36][37] . Furthermore, the activation of DA neurons correlates with the pauses of tonic discharge of ChINs, ex vivo [38][39][40] and in vivo 41 , promoting in turn, the disinhibition of MSNs activity 42,43 . In the DMS, both MSNs types respond to visual and tactile stimulation 44 . ...
... Therefore, ChINs will increase the inhibition towards MSNs in response to visual but not tactile stimulation 23,24 (Fig. 4G). However, when DA is released it will inhibit ChINs 34,42,43,68 resulting mainly in the disinhibition of MSNs visual responses (Fig. 4H). Due to this disinhibition, visual responses will be "unbraked", accelerating their responses (Fig. 3D, Table 2). ...
... 1C). It includes changes in the cell properties of both MSNs types in the presence of DA, as well as the known blockage of ChINs spiking activity when DA is released 42,43,68 . ...
The brain operates with simultaneous different sensory modalities in order to engage adaptive responses. However, the question of how (and where) multisensory information is integrated remains unanswered. In the dorsomedial striatum, single medium spiny neurons (MSNs) are excited by tactile and visual inputs; however, the mechanism which allows the integration of these responses and how they are shaped by dopamine is unknown.
Using in vivo optopatch-clamp recordings, we study how dopamine modulates tactile, visual and simultaneous bimodal responses in identified MSNs and their spontaneous activity. Results show that dopamine enhances bimodal responses, specifically in direct pathway MSNs, through the acceleration of the visual responses. We provide anatomical and computational evidence suggesting that this relies on the disinhibition of direct MSNs by a cell-type-specific corticostriatal pathway. Altogether, our in vivo , in silico and tracing results propose a new mechanism underlying the synchronization of multimodal information mediated by dopamine.
... This article is a US Government work. It is not subject to copyright under 17 USC It should also be noted that a recent studies indicate that D2-mediated pauses are longer lasting or more readily detected in ChIs in slices from DMS compared to DLS, due to stronger glutamate release in DLS that produces bursts interrupting the D2mediated pause (71,72). While it is unclear if this is the case in vivo, this difference could factor into how D2 receptors influence the function of dStr regions implicated in goal-directed versus habitual actions. ...
Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes
in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability,
dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs. In vivo electrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task.
... 25,26 Glutamate cotransmission also generates slower but discrete synaptic currents in the lateral CPu via metabotropic glutamate receptors (mGluRs). 27,28 GABA was identified as another DA neuron cotransmitter, eliciting GABA A responses in the dorsal Str 29 and NAc, 30,31 dependent on the expression of plasma membrane GABA transporter GAT1 30,32 and vesicular monoamine transporter VMAT2. 29 DA mediates discrete synaptic responses in the Str as well. ...
... DA neurons in the SN elicit D2R-mediated subsecond inhibitory synaptic responses in the CPu. 31 DA1/5R-mediated excitatory synaptic responses were first identified in the olfactory tubercle, 33 then in the lateral CPu. 27 These three neurotransmitters-identified as mediators of DA neuron synaptic transmission -engage five receptors: ionotropic glutamate receptors (iGluRs), mGluR1, DA D2R, DA D1/5 (D1-like) R, and GABA A R. 20,23,24,[27][28][29]31,[33][34][35] The corresponding synaptic actions can be categorized as either canonical synaptic transmission mediated by ion-channel-type receptors (iGluR and GABA A R) or as subsecond synaptic transmission mediated by G protein-coupled receptors (DAR and mGluR) activating effector channels to generate discrete synaptic currents, in contrast to volume transmission, which does not elicit discrete postsynaptic currents. ...
... DA neurons in the SN elicit D2R-mediated subsecond inhibitory synaptic responses in the CPu. 31 DA1/5R-mediated excitatory synaptic responses were first identified in the olfactory tubercle, 33 then in the lateral CPu. 27 These three neurotransmitters-identified as mediators of DA neuron synaptic transmission -engage five receptors: ionotropic glutamate receptors (iGluRs), mGluR1, DA D2R, DA D1/5 (D1-like) R, and GABA A R. 20,23,24,[27][28][29]31,[33][34][35] The corresponding synaptic actions can be categorized as either canonical synaptic transmission mediated by ion-channel-type receptors (iGluR and GABA A R) or as subsecond synaptic transmission mediated by G protein-coupled receptors (DAR and mGluR) activating effector channels to generate discrete synaptic currents, in contrast to volume transmission, which does not elicit discrete postsynaptic currents. ...
Dopamine neurons project to the striatum to control movement, cognition, and motivation via slower volume transmission as well as faster dopamine, glutamate, and GABA synaptic actions capable of conveying the temporal information in dopamine neuron firing. To define the scope of these synaptic actions, recordings of dopamine-neuron-evoked synaptic currents were made in four major striatal neuron types, spanning the entire striatum. This revealed that inhibitory postsynaptic currents are widespread, while excitatory postsynaptic currents are localized to the medial nucleus accumbens and the anterolateral-dorsal striatum, and that all synaptic actions are weak in the posterior striatum. Synaptic actions in cholinergic interneurons are the strongest, variably mediating inhibition throughout the striatum and excitation in the medial accumbens, capable of controlling their activity. This mapping shows that dopamine neuron synaptic actions extend throughout the striatum, preferentially target cholinergic interneurons, and define distinct striatal subregions.
... To further identify the mechanism driving this D1-resistant depolarization, we quantified the amplitude in the presence of various pharmacological agents. A recent study by Chuhma and colleagues reported a similar excitation in the dorsal striatum in response to optogenetic activation of DA terminals that was mediated by a combination of D1 and metabotropic glutamate type 1 (mglur1) receptors (Chuhma et al., 2018). Therefore, we repeated the experiment in the presence of both SCH-23390 (10 mM) and a mglur1 receptor antagonist, CPCOOEt (100 mM). ...
The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that regulates motivated behavior and affective states and plays an integral role in the development of alcohol-use disorder (AUD). The dorsal subdivision of the BNST receives dense dopaminergic input from the ventrolateral periaqueductal gray (vlPAG)/dorsal raphe (DR). To date, no studies have examined the effects of chronic alcohol on this circuit. Here, we used chronic intermittent ethanol exposure (CIE), a well-established rodent model of AUD, to functionally interrogate the vlPAG/DR-BNST dopamine circuit during acute withdrawal. We selectively targeted vlPAG/DR DA neurons in tyrosine hydroxylase-expressing transgenic adult male mice. Using ex vivo electrophysiology, we found hyperexcitability of vlPAG/DR DA neurons in CIE-treated mice. Further, using optogenetic approaches to target vlPAG/DR DA terminals in the dBNST, we revealed a CIE-mediated shift in the vlPAG/DR-driven excitatory-inhibitory ratio to a hyperexcitable state in dBNST. Additionally, to quantify the effect of CIE on endogenous DA signaling, we coupled optogenetics with fast-scan cyclic voltammetry to measure pathway-specific DA release in dBNST. CIE-treated mice had significantly reduced signal half-life, suggestive of faster clearance of DA signaling. CIE treatment also altered the ratio of vlPAG/DR DA -driven cellular inhibition and excitation of a subset of dBNST neurons. Overall, our findings suggest a dysregulation of vlPAG/DR to BNST dopamine circuit, which may contribute to pathophysiological phenotypes associated with AUD.
SIGNIFICANCE STATEMENT:
The dorsal bed nucleus of stria terminalis (dBNST) is highly implicated in the pathophysiology of alcohol use disorder and receives dopaminergic inputs from ventrolateral periaqueductal gray/dorsal raphe regions (vlPAG/DR). The present study highlights the plasticity within the vlPAG/DR to dBNST dopamine (DA) circuit during acute withdrawal from chronic ethanol exposure. More specifically, our data reveal that chronic ethanol strengthens vlPAG/DR-dBNST glutamatergic transmission while altering both DA transmission and dopamine-mediated cellular inhibition of dBNST neurons. The net result is a shift toward a hyperexcitable state in dBNST activity. Together, our findings suggest chronic ethanol may promote withdrawal-related plasticity by dysregulating the vlPAG/DR-dBNST DA circuit.
... Drd1 effects, mediated by Gα s -coupled pathways, have diverse impacts on neuronal channels in other cell types, raising the likelihood that currents in UBCs are also altered by Drd1 activation. Of special note for Drd1+ UBCs, dopamine might enhance mGluR1-mediated transient receptor potential channel (TRPC3) currents (Sekerková et al., 2013), as has been previously demonstrated for striatal cholinergic interneurons (Chuhma et al., 2018). If so, this mechanism would have synergistic effects with NMDAR-mediated current enhancement in response to Drd1 receptor activation. ...
While multiple monoamines modulate cerebellar output, the mechanistic details of dopaminergic signaling in the cerebellum remain poorly understood. We show that Drd1 dopamine receptors are expressed in unipolar brush cells (UBCs) of the mouse cerebellar vermis. Drd1 activation increases UBC firing rate and postsynaptic NMDA receptor-mediated currents. Using anatomical tracing and in situ hybridization, we test three hypotheses about the source of cerebellar dopamine. We exclude midbrain dopaminergic nuclei and tyrosine hydroxylase-positive Purkinje cells as potential sources, supporting the possibility of dopaminergic co-release from locus coeruleus (LC) axons. Using an optical dopamine sensor GRABDA, electrical stimulation, and optogenetic activation of LC fibers in the acute slice, we find evidence for monoamine release onto Drd1-expressing UBCs. Altogether, we propose that the LC regulates cerebellar cortex activity by co-releasing dopamine onto UBCs to modulate their response to cerebellar inputs. Purkinje neurons directly inhibit these Drd1-positive UBCs, forming a dopamine-sensitive recurrent vestibulo-cerebellar circuit.
... Another tier of functional modulation of dopamine nigral input is modulation of the activity of the cholinergic interneurons of the striatum. Through the use of optogenetic stimulation, slice electrophysiology, retrograde tracer injection, and pharmacological manipulations, a subset of SN neurons that project to the lateral dorsal striatum have been revealed to exert two effects on cholinergic interneurons, first from DA release and subsequently in response to glutamate release from the same neurons 100 . These neurons, via D2 receptors, first inhibit the cholinergic interneurons, and then due to their co-release of glutamate, promote a slow excitation via mGlur1 and partially via D1-like receptors coupled to transient receptor potential channels 3 and 7. ...
In addition to the well-known degeneration of midbrain dopaminergic neurons, enteric neurons can also be affected in neurodegenerative disorders such as Parkinson’s disease (PD). Dopaminergic neurons have recently been identified in the enteric nervous system (ENS). While ENS dopaminergic neurons have been shown to degenerate in genetic mouse models of PD, analyses of their survival in enteric biopsies of PD patients have provided inconsistent results to date. In this context, this review seeks to highlight the distinctive and shared factors and properties that control the evolution of these two sets of dopaminergic neurons from neuronal precursors to aging neurons. Although their cellular sources and developmental times of origin differ, midbrain and ENS dopaminergic neurons express many transcription factors in common and their respective environments express similar neurotrophic molecules. For example, Foxa2 and Sox6 are expressed by both populations to promote the specification, differentiation, and long-term maintenance of the dopaminergic phenotype. Both populations exhibit sustained patterns of excitability that drive intrinsic vulnerability over time. In disorders such as PD, colon biopsies have revealed aggregation of alpha-synuclein in the submucosal plexus where dopaminergic neurons reside and lack blood barrier protection. Thus, these enteric neurons may be more susceptible to neurotoxic insults and aggregation of α-synuclein that spreads from gut to midbrain. Under sustained stress, inefficient autophagy leads to neurodegeneration, GI motility dysfunction, and PD symptoms. Recent findings suggest that novel neurotrophic factors such as CDNF have the potential to be used as neuroprotective agents to prevent and treat ENS symptoms of PD.
