Corticostriatal pathways for bilateral sensorimotor functions

Corticostriatal pathways are essential for a multitude of motor, sensory, cognitive, and affective functions. They are mediated by cortical pyramidal neurons, roughly divided into two projection classes: the pyramidal tract (PT) and the intra-telencephalic tract (IT). These pathways have been the focus of numerous studies in recent years, revealing their distinct structural and functional properties. Notably, their synaptic connectivity within ipsi-and contralateral cortical and striatal microcircuits is characterized by a high degree of target selectivity, providing a means to regulate the local neuro-modulatory landscape in the striatum. Here, we discuss recent findings regarding the functional organization of the PT and IT corticostriatal pathways and its implications for bilateral sensorimotor functions.


Introduction
The basal ganglia (BG) are a collection of anatomically and functionally interconnected subcortical nuclei that play a crucial role in the learning, optimization, selection, and execution of appropriate actions from the enormous behavioral repertoire [1].
The main entry station of the BG circuitry is the striatum, receiving multiple excitatory, inhibitory, and neuromodulatory inputs arising from diverse brain regions, including most cortical areas.The corticostriatal projections follow a topographical arrangement, giving rise to structurally and functionally segregated striatal territories.The striatum is therefore strategically placed to act as a "hub" for convergence and integration of multiple information streams [2].Such integration of sensory information, internal brain states, and motor commands is essential to produce successful adaptive behavior.Furthermore, this operation is constantly improved through reinforcement learning, which depends on the integration of sensorimotor information and reinforcement-related signals associated with specific actions.
The striatum consists of a large majority of GABAergic projection neurons, the medium spiny neurons (MSNs), and a small heterogeneous population of interneurons [3,4].MSNs can be subdivided into two classes based on their connectivity and expression of dopamine (DA) receptors: D 1 R-expressing "direct" pathway MSNs (dMSNs) and D 2 R-expressing "indirect" pathway MSNs (iMSNs).These MSN types play complex complementary roles in neural computations carried out in the striatum [5e7].Proper function of the BG depends on a delicate balance between the direct and indirect pathways, which is partially achieved through dopaminergic neuromodulation arising from the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA).Correspondingly, dysregulation of dopaminergic signaling in the BG underlies the clinical manifestations of several neurological and psychiatric disorders [8,9].In addition to the majority of MSNs, the striatal circuitry contains a small and diverse population of GABAergic interneurons (GINs) [3,4], and a unique population of cholinergic interneurons (ChINs).
Approximately half of the primary glutamatergic excitatory inputs to the striatum are projections from the neocortex, while other less well characterized projections are from the thalamus [10].Cortical projections to the striatum originate from two distinct classes of pyramidal neurons: those with only intratelencephalic connections (IT [intratelencephalic] neurons; located in layer III and upper layer V), and those projecting to extratelencephalic targets via the corticospinal and corticobulbar tracts (PT [pyramidal tract] neurons; located in lower layer V) while sending axon collaterals to the striatum (Figure 1).These cortical pyramidal neuron classes differ in their morphology, neurochemistry, function, and synaptic connectivity [11,12].A crucial aspect regarding these pathways is that while PT neurons project only to the ipsilateral striatum, IT neurons project to both striatal hemispheres [11e13].In this review, we discuss recent studies which have contributed to advancing our understanding of the interhemispheric sensorimotor dialogue in the striatum.

Bilateral corticostriatal afferents
The striatum receives monosynaptic inputs from multiple brain regions including the cortex, the thalamus, the brainstem, and other BG nuclei [3].Whereas most of these input pathways are ipsilateral, one striking exception is the corticostriatal IT pathway, which targets both striatal hemispheres.Pyramidal cells constituting the IT pathway consist of several molecularlydefined subtypes, some of which project only to the contralateral cortical hemisphere, while others project to both cortex and striatum [14,15].Contralateral corticostriatal input from primary sensory cortices is relatively sparse compared to motor and prefrontal regions [16e18].A recent study in mice showed that the amount of contralateral IT projections increases along the posterior-anterior cortical axis, with prefrontal cortical regions exhibiting the strongest and most symmetrical contralateral projections [19].The other corticostriatal pathway is mediated by PT pyramidal neurons, which target the ipsilateral striatum as well as other subcortical targets including nuclei in the BG, thalamus, brainstem, and spinal cord (Figure 1).The PT population is also diverse, displaying different connectivity patterns with subcortical structures [15,20].Of note, the "hyperdirect" pathway between the cortex and the subthalamic nucleus [21], and cortical projections to the substantia nigra pars reticulata [22], are mediated by ipsilateral corticostriatal projections that are part of the PT pathway [23,24].

Synaptic target selectivity in PT and IT pathways
Pyramidal neurons of the PT and IT pathways exhibit target selectivity in their intracortical connections, with high recurrent connectivity between IT cells and from IT to PT cells (Figure 2), and relatively sparse connectivity originating from PT cells [12,25,26].The two populations also display different connectivity with cortical GABAergic interneurons, with PT neuronsdin particular thick-tufted pyramidal neuronsdbeing robustly interconnected via disynaptic inhibition [27], unlike the corticocallosal IT cells [28].In the striatum, the PT and IT pathways provide excitatory inputs to both MSN types as well as to GABAergic interneurons (Figure 2).However, these synaptic connections exhibit target selectivity in terms of their strength, connection probability, and plasticity [4,29e31].Whereas both dMSNs and iMSNs receive cortical inputs, anatomical studies suggested a bias in innervation, with dMSNs Anatomy of the PT and IT corticostriatal pathways.(a) Schematic depicting the origin and projections of the pyramidal tract (PT) and intratelencephalic (IT) pathways in the cerebral cortex.PT pyramidal neurons are primarily located in lower layer V of the neocortex and send axonal projections to distant targets in the brainstem and the spinal cord, with axonal collaterals to the ipsilateral striatum.IT neurons, located in layer III and upper layer V of the neocortex, send axonal projections to the contralateral cortex and to the ipsi-and contralateral striatal hemispheres.(b) Schematic of the PT and IT corticostriatal pathways.Pyramidal neurons of the PT pathway (in red, left) provide innervation only to the ipsilateral striatum, as well as to other BG nuclei, as collaterals from axons en route to the brainstem and the spinal cord.Pyramidal neurons of the IT pathway (in blue, right) provide innervation to both striatal hemispheres.Some structures have been omitted on the right side for visual clarity.Abbreviations: STN, subthalamic nucleus; GPe, external globus pallidus; GPi, internal globus pallidus; SN, substantia nigra.
being preferentially targeted by IT neurons and iMSNs by PT neurons [32,33].Later functional studies using optogenetic activation of corticostriatal terminals showed comparable responses to IT and PT pathway stimulation in both MSN types [34], with relative strengths of corticostriatal inputs to dMSNs and iMSNs depending on the presynaptic cortical region and laterality [29].
Striatal GABAergic interneurons also receive cortical input, with all classes tested thus far responding to electrical and optogenetic stimulation of corticostriatal projections from both hemispheres [4,29e31,35].Cortical inputs to the different GABAergic interneuron classes are not homogeneous and vary strongly in their connection rates, release probabilities, and synaptic strengths.Optogenetic activation of corticostriatal terminals (both ipsi-and contralateral) in the mouse striatum showed that parvalbumin expressing interneurons had the strongest synaptic responses from all tested striatal populations, including MSNs and other interneurons [29].The different types of striatal neurons are characterized by distinct membrane resonance properties that shape their preferred response to cortical inputs [36], acting as band-pass filters of corticostriatal input.Mirroring the diversity of intrinsic properties, GABAergic interneurons have also been shown to exhibit different rules for spike timedependent corticostriatal plasticity than those of MSNs and ChINs [30].
A special case is the population of ChINs, constituting the only non-GABAergic striatal neuron type.ChINs receive cortical inputs primarily from the PT pathway, with very sparse inputs from the IT pathway [37], as seen also in the lack of inputs from the contralateral cortical hemisphere [29] (Figure 2).This difference between PT and IT innervation of ChINs directly Target selectivity of PT and IT pathways in the striatal microcircuit.Schematic of ipsi-and contralateral corticostriatal projections in the dorsal striatum, mediated by the PT and IT pathways.PT projections (in black) target all known striatal neuron types in the ipsilateral striatum, whereas IT cells (in gray) target ipsi-and contralateral striatum as well as the contralateral cortex.Cholinergic interneurons (ChINs, in red) receive primarily ipsilateral cortical input from the PT pathway.MSNs of both types (in blue) and GABAergic interneurons (GINs, in green) receive excitatory inputs from both PT and IT cells.The GIN population is grouped here for simplicity, but note the large diversity of this group, as previously described [3,4,29].ChINs target the axons of midbrain dopamine terminals (in orange), which co-release glutamate, GABA, and 5-HT.
affects the integration of cortical input by MSNs, resulting in biphasic excitatory responses to synchronous activation of the PT, but not IT, corticostriatal pathway [37].Synchronized activation of ChINs induces also inhibitory responses in MSNs via polysynaptic interactions [38].

Implications on bilateral neuromodulation
In addition to the glutamatergic and GABAergic interactions described above, multiple neuromodulatory systems provide extensive input to the striatum and are therefore well positioned to regulate its operation [3].These include DA from the midbrain, acetylcholine (ACh) from striatal ChINs and brainstem nuclei, serotonin (5-HT) from the raphe nuclei, and histamine from the hypothalamus.The interplay between multiple neuromodulators simultaneously shaping corticostriatal computations argues in favor of the "multiple critics, multi-objective optimization" models of the BG [1].Among these neuromodulators, the role of DA in orchestrating the function of the striatum is the best established.DA has been shown to play the role of an "external critic," providing feedback signals to regulate plasticity processes underlying learning in the striatum [39].Indeed, dopaminergic neurons' firing activity encodes reward prediction error (RPE, the mismatch between expected and experienced reward) [39e41], and is thus crucial in reinforcement learning.Besides its role in reinforcement learning, DA cell activity has also been shown to be correlated to various motor parameters, including the initiation, termination, and kinetics of movements [42,43].This functional heterogeneity is mirrored by the cellular diversity of midbrain DA neurons [44].
New work has also explored the role of DA in actionoutcome encoding during lateralized goal-directed behavior.In a recent study, DA release was monitored in the dorsomedial striatum of rats while they engaged in a task in which they had to perform two possible actions associated with two different outcomes [45].A lateralized DA signal was observed when the rats performed goal-directed actions, which reflected and tracked the development of the action-outcome association.This lateralized DA signal was shown to be updated by a DA action value signal and by an RPE upon exposure to the outcome, both of which are bilaterally broadcast.These results highlight that DA plays multiple roles during goal-directed behavior.Notably, some of the signals conveyed through DA release, such as information about action value and RPE, are broadcast bilaterally, while some others, such as the strength of the action-outcome association, display striking lateralization.Interestingly, lateralization of DA dynamics can occur in specific striatal territories, as has been observed in the dorsal striatum but not in the ventral striatum during execution of a visual decision-making task [46].
An intriguing possibility is that the lateralization observed in DA signals conveyed to the striatum could emerge in the local microcircuit.As discussed in the preceding section, ChINs receive inputs primarily from the ipsilateral cortex via the PT pathway.This unilateral control of ChINs could represent a means to shape the activity of other neuromodulators in a single striatal hemisphere.2).However, the function of these interactions in vivo has only started to be directly tested in the last few years.A recent study used fiber photometry to monitor DA and ACh dynamics in the dorsal striatum in mice walking on a treadmill [56].It was observed that rewards evoked changes in DA and ACh release, with a sharp increase in DA and a biphasic increase-decrease ACh response, in which ACh rekease preceded the DA peak.However, local pharmacological blockade of DA receptors did not affect the dynamics of ACh release.Moreover, pharmacologically blocking nicotinic receptors or knocking out the b2 nicotinic receptor subunit in DA neurons did not perturb DA and ACh dynamics.These results provide evidence against neuromodulatory coordination between DA and ACh in dorsal striatum arising from direct intrastriatal interactions between DA and ACh in vivo.It is suggested that ACh fluctuations are instead controlled by extrastriatal glutamatergic afferents.Another recent study using fiber photometry to monitor the release of ACh and DA in the ventrolateral striatum during a reward-based decision-making task showed that these two neuromodulators' release shows mostly anticorrelated transients, and that their dynamics are influenced by multiple behavioral variables [57].However, DA release dynamics and reward prediction error (RPE) encoding were not disrupted by perturbations of ACh release by ChINs.Nonetheless, selective ablation of D 2 receptors in ChINs showed that loss of DA regulation of ChIN activity impairs decision-making.Taken together, these studies argue against the physiological relevance of local DA-ACh interactions in the striatum in vivo.However, another new study monitoring DA release in the nucleus accumbens of awake, unrestrained rats while simultaneously measuring or manipulating ChIN activity [58] reported that ChIN stimulation evoked DA release in vivo.In addition, while rats engaged in an operant conditioning task [52], it was shown that fast ramps in ChIN activity and DA release co-occur during approach behaviors to either start a trial or to collect rewards.Notably, the increase in DA release co-occurring with ChIN activity ramps was independent of firing activity of DA neurons in the VTA.Furthermore, pharmacological blockade of nicotinic receptors disrupted performance in the task.These results support the role of ChINs as regulators of DA release during motivated behavior.
The divergent observations from the studies discussed above call for further work aimed to clarify if the interaction between DA and ACh in vivo varies across specific territories of the local striatal microcircuit and across behavioral contexts.

Interhemispheric striatal sensorimotor integration
As discussed above, the connectivity of the striatum puts it in a strategic position to integrate multimodal information from both hemispheres.The computations performed on the multiple information streams reaching the striatal circuits can then support the production of appropriate motor commands to drive behavior, with the ensuing sensory feedback.This loop of sensory inflow and corresponding motor adjustment is thought to allow animals to successfully execute complex bilaterallycoordinated movements.
In previous studies from our laboratory using whole-cell patch-clamp recordings in anesthetized mice during presentation of tactile and visual stimuli, we have shown that MSNs in the dorsal striatum integrate sensory information arising from both cerebral hemispheres [2,18,59].This sensory integration is disrupted by DA depletion, with distinct effects on the laterality of responses [60].In a following study, we extended this approach to investigate the sensorimotor integration in the striatum of awake behaving animals [61].We showed that bilateral sensory responses in MSNs are modulated by motor activity, consistent with recent work showing that the interhemispheric coordination mediated by the IT pathway is brain-state dependent [62].Moreover, it was revealed that DA depletion differentially affected sensorimotor integration in MSN subtypes, and disrupted the discrimination between ipsi-and contralateral sensory stimulation, further supporting the notion of selective targeting of the direct and indirect pathways in the striatal circuitry [29].The conspicuous effect of motor activity in sensory integration in the dorsal striatum revealed in the studies discussed above strongly supports the view that the striatum is involved in a sensorimotor loop regulating ongoing movement.
Skillful goal-directed movements rely on the integration of sensorimotor information across many cortical and subcortical modules.Moreover, when a motor program involves bilateral coordination, the orchestration of movement depends on interhemispheric dialogue.As there are no direct projections between the left and right striatal hemispheres, the bilateral coordination of movement likely depends on interhemispheric corticostriatal projections from sensorimotor cortices via the IT pathway.A recent study explored the contribution of this pathway to behavior by combining cortical and striatal lesions, pathway-specific optogenetic manipulations, and extracellular recordings to study the dynamics of the corticostriatal pathways in rats during a task involving bilaterally-coordinated forelimb movements [63].This study found that unilateral lesions in the dorsolateral striatum impair movement in a single forelimb, thereby affecting bilateral coordination.However, movement initiation was not disrupted.It was also observed that selective unilateral optogenetic activation of IT corticostriatal projections produced increased bilateral movement duration and coordination.These results are consistent with another recent study in mice showing that skilled forelimb movement duration can be shortened by inactivating IT neurons in the primary motor cortex [64].Overall, these findings suggest that the initiation of bilaterally-coordinated movements depends on motor areas of the cortex, which then recruit the sensorimotor striatum bilaterally via the IT pathway to modulate ongoing movement.Furthermore, cortical projection cell types appear to carry separable components of motor commands, and this fine-tuning of ongoing movement vigor may reflect the selective targeting of dMSNs and iMSNs by PT and IT pathways [65].
Finally, the anatomical and functional divergence in the corticostriatal pathways not only has implications for motor control in the physiological state, but is also involved in the pathophysiology of disorders affecting the BG.Parkinson's disease (PD) is characterized by BG dysfunction due to DA depletion, which is thought to lead to motor symptoms by disrupting the motor commands sent from motor cortices to the final effector circuits in the brainstem and spinal cord.Furthermore, it has been suggested that distinct cortical neuron subtypes may be affected differently in PD.In accordance with this view, studies in monkeys performing a step-tracking arm movement task have shown that the experimental induction of parkinsonism substantially impairs the movement-related parameters of spiking activity in the primary motor cortex [66].In these experiments, a striking selectivity in PT neurons was observed, while IT neurons were comparatively spared.These results are consistent with more recent work using two-photon calcium imaging and optogenetic manipulation of primary motor cortex neurons in a mouse model of PD [67].Parkinsonian mice displayed impaired performance in a reach-to-grasp task, which could be partially restored by optogenetic stimulation of the primary motor cortex.The disruption of neuronal activity in experimentally induced parkinsonism was observed primarily in PT neurons.These observations support the notion that the motor symptoms of PD may result from a pathway-specific disruption in the generation of appropriate motor commands by the motor cortex.

Outlook
Recent technological advances allowing selective monitoring and manipulation of corticostriatal pathways and neuromodulatory systems in the awake behaving animal have begun to shed light on how BG circuits operate during bilaterally-coordinated behavior.We expect that upcoming studies using these novel techniques in combination with multiple behavioral assays will clarify the puzzling divergences between reports from investigations of the striatal microcircuit conducted ex vivo and in vivo, especially regarding the interplay of neuromodulators for the control of striatal function.This study used anatomical tracing to investigate the topography of ipsi-and contralateral projections to the striatum from different cortical regions.It is shown that the sensory and motor cortices project heavily to the ipsilateral striatum, but much less to the contralateral.In contrast, frontal cortical areas display a much less lateralized projection to both striatal hemispheres.These results highlight that the degree of lateralization in corticostriatal projections depends on the functional specialization of cortical and striatal territories * * .Morgenstern NA, Isidro AF, Israely I, Costa RM: Pyramidal tract neurons drive amplification of excitatory inputs to striatum through cholinergic interneurons.Sci Adv 2022, 8: eabh4315.This study shows using ex vivo recordings that striatal ChINs receive excitatory inputs primarily from PT projections and only very sparse excitation from IT cells.Using optogenetic stimulation of PT terminals it was shown that PT input to ChINs induced feedforward excitation in MSNs mediated by nicotinic receptors, resulting in a secondary excitatory response that was absent in IT terminal stimulation.The study demonstrates the target selectivity of corticostriatal pathways and the way it shapes striatal projections  4095.Using in vivo whole cell recordings and two-photon imaging, this study shows that interhemispheric coupling mediated by cortico-callosal cells of the IT pathway is brain-state dependent.The degree of coupling between the two cortical hemispheres was reduced during whisking while elevated in quiet wakefulness.Optogenetic and chemogenetic inhibition of IT cells reduced interhemispheric correlation, especially during quiescence 63 * * .Pimentel-Farfan AK, Báez-Cordero AS, Peña-Rangel TM, Rueda-Orozco PE: Cortico-striatal circuits for bilaterally coordinated movements.Sci Adv 2022, 8:eabk2241.This study directly addressed the contribution of the bilateral corticostriatal projections via the IT pathway to ongoing bilaterally coordinated movement.It is shown that the initiation of bilaterally coordinated movement depends on the motor cortices, which recruit the sensorimotor striatum in both hemispheres.Their results suggest that the sensorimotor striatum is not crucial for movement initiation, but for the modulation of ongoing movement through sensory feedback.This study shows the involvement of pyramidal neurons of the PT pathway in the primary motor cortex in motor impairments caused by DA depletion.The authors used two-photon calcium imaging and optogenetic manipulation of cortical neurons in vivo to reveal that selective activation of layer V PT neurons improved the performance of DA-depleted mice in a reach-to-grasp task.

Figure 2
Figure 2 38. English DF, Ibanez-Sandoval O, Stark E, Tecuapetla F, Buzsáki G, Deisseroth K, Tepper JM, Koos T: GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons.Nat Neurosci 2011, 15:123-130.39.Berke JD: What does dopamine mean?Nat Neurosci 2018, 21: 787-793.40.Schultz W, Dayan P, Montague PR: A neural substrate of prediction and reward.Science 1997, 275:1593-1599.41 * .Shikano Y, Yagishita S, Tanaka KF, Takata N: Slow-rising and fast-falling dopaminergic dynamics jointly adjust negative prediction error in the ventral striatum.Eur J Neurosci 2023, https://doi.org/10.1111/ejn.15945.This study used fiber photometry to monitor DA dynamics in the ventral striatum in a task where mice perform trials with different degrees of reward expectation.It is shown that there is a monotonic relationship between the DA dip amplitude upon unexpected reward omissions and the degree of reward expectation.42.da Silva JA, Tecuapetla F, Paixão V, Costa RM: Dopamine neuron activity before action initiation gates and invigorates future movements.Nature 2018, 554:244-248.43.Engelhard B, Finkelstein J, Cox J, Fleming W, Jang HJ, Ornelas S, Koay SA, Thiberge SY, Daw ND, Tank DW, et al.: Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons.Nature 2019, 570:509-513.44.Tiklová K, Björklund ÅK, Lahti L, Fiorenzano A, Nolbrant S, Gillberg L, Volakakis N, Yokota C, Hilscher MM, Hauling T, et al.: Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development.Nat Commun 2019, 10:581.45 * * .Hart G, Burton TJ, Nolan CR, Balleine BW: Striatal dopamine encodes the relationship between actions and reward.bio-Rxiv 2023, https://doi.org/10.1101/2022.01.31.478585.This study reveals the development of a lateralized DA signal that tracks the strength of action-outcome associations while rats learn a goal-directed behavior.This signal is updated by a DA action value signal during the action, and by an RPE after exposure to the outcome, both broadcast bilaterally.46 * .Moss MM, Zatka-Haas P, Harris KD, Carandini M, Lak A: Dopamine axons in dorsal striatum encode contralateral visual stimuli and choices.J Neurosci 2021, 41:7197-7205.This study used fiber photometry to record the activity of DA axons in the striatum while mice performed a visual decision-making task.It is shown that the activity of DA axons innervating the dorsomedial striatum is lateralized, with responses to contralateral visual stimuli and contralateral rewarded actions.In contrast, DA axons innervating the ventral striatum respond to both ipsi-and contralateral stimuli 47.Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ: Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons.Neuron 2012, 75:58-64.48.Dorst MC, Tokarska A, Zhou M, Lee K, Stagkourakis S, Broberger C, Masmanidis S, Silberberg G: Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner.Nat Commun 2020, 11:5113.
, Phillips JW, Guo J-Z, Martin KA, Hantman AW, Dudman JT: Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes.Sci Adv 2022, 8, eabj5167.This study combined high-density extracellular recordings from motor cortex and striatum with pathway-specific manipulations to reveal that cortical projections arising from PT and IT neurons carry distinct components of motor control commands during skilled forelimb movement in mice.65 * .Lopez-Huerta VG, Denton JA, Nakano Y, Jaidar O, Garcia-Munoz M, Arbuthnott GW: Striatal bilateral control of skilled forelimb movement.Cell Rep 2021, 34, 108651.This study shows that selective optogenetic manipulation of striatal D1and D2-expressing MSNs in dorsolateral striatum has differential effects on kinematic parameters during skilled unilateral forelimb movement in mice.Its results also highlight that contributions from both hemispheres are important for skilled unilateral forelimb movements 66. Pasquereau B, DeLong MR, Turner RS: Primary motor cortex of the parkinsonian monkey: altered encoding of active movement.Brain 2016, 139:127-143.67 * .Aeed F, Cermak N, Schiller J, Schiller Y: Intrinsic disruption of the M1 cortical network in a mouse model of Parkinson's disease.Mov Disord 2021, 36:1565-1577.
Recent studies have explored the local interactions of DA with other neuromodulators in the striatum, especially ACh.Ex vivo slice experiments have provided evidence that DA and ACh regulate each other's release in the striatum: ACh, released by ChINs, can trigger DA release through direct axonal depolarization mediated by nicotinic receptors [47], while DA in turn can inhibit ChINs and the release of ACh via D 2 receptors [48e50].The release of DA mediated by synchronous activation of ChINs can take place in response to activation of cortical terminals [51].These interactions suggest that DA release in the striatum can be controlled in at least two different ways [52]: propagation of action potentials from DA cell bodies, and activation of nicotinic receptors in DA axons by local ChINs.In addition, DA terminals have been shown to co-release 5-HT [53], GABA, and glutamate [54,55].These specific features suggest that corticostriatal inputs to ChINs, primarily from the PT pathway, are in a position to orchestrate the neuromodulatory landscape in the ipsilateral striatum (Figure 18. Reig R, Silberberg G: Distinct corticostriatal and intracortical pathways mediate bilateral sensory responses in the striatum.Cerebr Cortex 2016, 26:4405-4415.
Intrinsic dopamine and acetylcholine dynamics in the striatum of mice.Nature 2023, https://doi.org/10.1038/s41586-023-05995-9.This study used fiber photometry to address the dynamics of DA and ACh in the dorsal striatum in awake mice.Its results provide evidence that the neuromodulatory coordination between DA and ACh in dorsal striatum does not arise from direct intrastriatal interactions between DA and ACh.It is suggested that ACh fluctuations are instead controlled by Dopamine and glutamate regulate striatal acetylcholine in decision-making.Nature 2023, https://doi.org/10.1038/s41586-023-06492-9.Using fiber photometry to simultaneously monitor the release of DA and ACh in the ventrolateral striatum in vivo, this study reveals that DA and ACh release during decision making is mostly anticorrelated and displays complex dynamics influenced by ongoing behavior.Contrary to the prediction based on in vitro studies, it is proposed that disruption of ACh release by ChINs does not impair DA release dynamics in the striatum.Ongoing movement controls sensory integration in the dorsolateral striatum.Nat Commun 2023, 14:1004.This study shows that MSNs in the dorsolateral striatum encode both ipsi-and contralateral sensory stimulation in the awake behaving mouse, and that the integration of these sensory responses is modulated by motor activity.It is also shown that bilateral sensorimotor integration is differentially disrupted in MSNs after DA depletion