Biology subjects

Costa, R. M.

Publications and source records attributed to Costa, R. M..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Dissociable roles of thalamic nuclei in the refinement of reaches to spatial targets

Reaches are complex movements that are critical for survival, and encompass the control of different aspects such as direction, speed, and endpoint precision. Complex movements have been postulated to be learned and controlled through distributed motor networks, of which the thalamus is a highly connected node. Still, the role of different thalamic circuits in learning and controlling specific aspects of reaches has not been investigated. We report dissociable roles of two distinct thalamic nuclei - the parafascicular (Pf) and ventroanterior/ventrolateral (VAL) nuclei - in the refinement of spatial target reaches in mice. Using 2-photon calcium imaging in a head-fixed joystick task where mice learned to reach to a target in space, we found that glutamatergic neurons in both areas were most active during reaches early in learning. Reach-related activity in both areas decreased late in learning, as movement direction was refined and reaches increased in accuracy. Furthermore, the population dynamics of Pf, but not VAL, covaried in different subspaces in early and late learning, but eventually stabilized in late learning. The neural activity in Pf, but not VAL, encoded the direction of reaches in early but not late learning. Accordingly, bilateral lesions of Pf before, but not after learning, strongly and specifically impaired the refinement of reach direction. VAL lesions did not impact direction refinement, but instead resulted in increased speed and target overshoot. Our findings provide new evidence that the thalamus is a critical motor node in the learning and control of reaching movements, with specific subnuclei controlling distinct aspects of the reach early in learning.

neuroscience↗

bioRxiv2023

Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction.

BackgroundRenin-angiotensin (Ang II)-aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS). MethodsMale C57/BL6J or mt-keima mice (6-8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg). ResultsEthanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1 (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mt-keima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H2O2 bioavailability. These responses were prevented by losartan. ConclusionAT1 receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H2O2 bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking.

pharmacology and toxicology↗

bioRxiv2023

NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration

BackgroundHigh levels of testosterone (Testo) are associated with cardiovascular risk by increasing reactive oxygen species (ROS) formation. NADPH oxidases (NOX) are the major source of ROS in the vasculature in cardiovascular diseases. NOX4 is a unique isotype, which produces hydrogen peroxide (H2O2), and its participation in cardiovascular biology is controversial. So far, it is unclear whether NOX4 protects from Testo-induced endothelial injury. Thus, we hypothesized that supraphysiological levels of Testo induce endothelial NOX4 expression to attenuate endothelial injury. MethodsHuman Mesenteric Vascular Endothelial Cells (HMEC) and Human Umbilical Vein Endothelial Cells (HUVEC) were treated with Testo (10-7 M) with or without a NOX4 inhibitor [GLX351322 (10-4 M)]. In vivo, 10-week-old C57Bl/6J male mice were treated with Testo (10 mg/kg) for 30 days to study endothelial function. ResultsTesto increased mRNA and protein levels of NOX4 in HMEC and HUVEC. Testo increased superoxide anion (O2-) and H2O2 production, which were abolished by NOX1 and NOX4 inhibition, respectively. Testo also attenuated bradykinin-induced NO production, which was further impaired by NOX4 inhibition. In vivo, Testo decreased H2O2 production in aortic segments and triggered endothelial dysfunction [decreased relaxation to acetylcholine (ACh)], which was further impaired by GLX351322 and by a superoxide dismutase and catalase mimetic (EUK134). Finally, Testo led to a dysregulated endothelial cells migration, which was exacerbated by GLX351322. ConclusionThese data indicate that supraphysiological levels of Testo increase the endothelial expression and activity of NOX4 to counterbalance the deleterious effects caused by Testo in endothelial function.

pharmacology and toxicology↗

bioRxiv2023

RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease

All brain areas affected in Parkinsons disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A-expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

neuroscience↗

bioRxiv2023

Exploration biases how forelimb reaches to a spatial target are learned

The brain can learn to generate actions, such as reaching to a target, using different movement strategies. Understanding how different variables bias which strategies are learned to produce such a reach is important for our understanding of the neural bases of movement. Here we introduce a novel spatial forelimb target task in which perched head-fixed mice learn to reach to a circular target area from a set start position using a joystick. These reaches can be achieved by learning to move into a specific direction or to a specific endpoint location. We find that mice gradually learn to successfully reach the covert target. With time, they refine their initially exploratory complex joystick trajectories into controlled targeted reaches. The execution of these controlled reaches depends on the sensorimotor cortex. Using a probe test with shifting start positions, we show that individual mice learned to use strategies biased to either direction or endpoint-based movements. The degree of endpoint learning bias was correlated with the spatial directional variability with which the workspace was explored early in training. Furthermore, we demonstrate that reinforcement learning model agents exhibit a similar correlation between directional variability during training and learned strategy. These results provide evidence that individual exploratory behavior during training biases the control strategies that mice use to perform forelimb covert target reaches.

neuroscience↗

bioRxiv2023

Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice

BackgroundObesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity. MethodsWe exposed male and female mice to a high-fat diet (HFD) for 12 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated. ResultsMale mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase. Finally, aortae from obese female mice, but not male, responded prematurely to Rho-kinase inhibitor, which was accompanied by a suppressed Rho-kinase activation, measured by western blot. ConclusionIn obesity, female mice demonstrate a vascular protective mechanism - suppression of vascular Rho-kinase - to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.

physiology↗

bioRxiv2023

Progranulin maintains blood pressure and vascular tone dependent on EphrinA2 and Sortilin1 receptors and eNOS activation

BackgroundThe mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin (PGRN) displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether PGRN sustains the vascular tone that helps regulate blood pressure. MethodsWe used male and female C57BL6/J wild type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) to understand the impact of PGRN on vascular contractility and blood pressure. ResultsWe found that male and female PGRN-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which are restored by supplementing the mice with recombinant PGRN (rPGRN). In ex vivo experiments, rPGRN attenuated the vascular contractility to noradrenaline in male and female PGRN+/+ arteries, which was blunted by blocking EphrinA2 or Sortlin1. To understand the mechanisms whereby PGRN evokes anti-contractile effects, we inhibited endothelial factors. L-NAME [nitric oxide (NO) synthase (NOS) inhibitor] prevented the PGRN effects, whereas indomethacin (cyclooxygenases inhibitor) only affected the contractility in arteries incubated with vehicle, indicating the PGRN increases nitric oxide and decreases contractile prostanoids. Finally, rPGRN induced endothelial NOS (eNOS) phosphorylation and NO production in isolated mesenteric endothelial cells. ConclusionCirculating PGRN regulates vascular tone and blood pressure via EphrinA2 and Sortlin1 receptors and eNOS activation. Collectively, our data suggest that deficiency in PGRN is a cardiovascular risk factor and that PGRN might be a new therapeutic avenue to treat high blood pressure. Clinical PerspectiveWhat is new? O_LIPGRN displays vascular anti-contractile effects dependent on EphrinA2 and Sortilin1 receptors and nitric oxide formation in male and female C_LIO_LIDeficiency in PGRN triggers high blood pressure and induces vascular dysfunction characterized by hypercontractility to noradrenaline C_LIO_LIPGRN supplementation restores blood pressure and vascular dysfunction in PGRN-deficient mice C_LI What are the clinical implications? O_LIPGRN deficiency is associated with neurodegenerative diseases including neuronal ceroid lipofuscinosis and frontotemporal dementia (FTD). Our study reveals that a lack of PGRN might be associated with vascular dysfunction and high blood pressure C_LIO_LISupplementation with PGRN might be a potential therapeutic route to treat high blood pressure and diseases associated with vascular dysfunction C_LIO_LIReduction in PGRN might be a target to screen for higher cardiovascular risk C_LI

pharmacology and toxicology↗

bioRxiv2022

Corticothalamic Neurons in Motor Cortex Have a Permissive Role in Motor Execution

The primary motor cortex (M1) is a central hub for motor learning and execution. M1 is composed of heterogeneous cell types, many exhibiting varying relationships to movement. Here, we employed an unbiased screen to tag active neurons at different stages of performance of a motor task. We characterized the relative cell type composition of active neurons across training and identified one cell type consistently enriched as training progressed: corticothalamic neurons (M1CT). Using two-photon calcium imaging, we found that M1CT activity is largely suppressed during movement, and this negative correlation with movement scales with movement vigor and augments with training. Closed-loop optogenetic manipulation of this population revealed that increasing M1CT activity during forelimb movement significantly hinders execution, an effect that became stronger with training. Similar optogenetic manipulations, however, had little effect on locomotion. In contrast to M1CT neurons, we observed that M1 corticospinal neurons positively correlate with movement, and that this positive correlation increases with learning. Finally, by examining the connectivity between M1CT and corticospinal neurons, we uncovered that M1CT neurons can suppress M1 corticospinal activity via feedforward inhibition, and that this inhibition scales with training. These results identify a novel permissive role of corticothalamic neurons in movement execution through suppression of inhibition of corticospinal neurons.

neuroscience↗

bioRxiv2022

Dynamic refinement of behavioral structure mediates dopamine-dependent credit assignment

Animals exhibit a diverse behavioral repertoire when exploring new environments and can learn which actions or action sequences produce positive outcomes. Dopamine release upon encountering reward is critical for reinforcing reward-producing actions1-3. However, it has been challenging to understand how credit is assigned to the exact action that produced dopamine release during continuous behavior. We investigated this problem with a novel self-stimulation paradigm in which specific spontaneous movements triggered optogenetic stimulation of dopaminergic neurons. Dopamine self-stimulation rapidly and dynamically changes the structure of the entire behavioral repertoire. Initial stimulations reinforced not only the stimulation-producing target action, but also actions similar to target and actions that occurred a few seconds before stimulation. Repeated pairings led to gradual refinement of the behavioral repertoire to home in on the target. Reinforcement of action sequences revealed further temporal dependencies of refinement. Action pairs spontaneously separated by long time intervals promoted a stepwise credit assignment, with early refinement of actions most proximal to stimulation and subsequent refinement of more distal actions. Thus, a retrospective reinforcement mechanism promotes not only reinforcement, but gradual refinement of the entire behavioral repertoire to assign credit to specific actions and action sequences that lead to dopamine release.

neuroscience↗

bioRxiv2022

Motor cortical influence relies on task-specific activity covariation

During limb movement, spinal circuits facilitate the alternating activation of antagonistic flexor and extensor muscles. Yet antagonist cocontraction is often required to stabilize joints, like when loads are handled. Previous results suggest that these different muscle activation patterns are mediated by separate flexion- and extension-related motor cortical output populations, while others suggest recruitment of task-specific populations. To distinguish between hypotheses, we developed a paradigm in which mice toggle between forelimb tasks requiring antagonist alternation or cocontraction and measured activity in motor cortical layer 5b. Our results conformed to neither hypothesis: consistent flexion- and extension-related activity was not observed across tasks, and no task-specific populations were observed. Instead, activity covariation among motor cortical neurons dramatically changed between tasks, thereby altering the relation between neural and muscle activity. This was also observed specifically for corticospinal neurons. Collectively, our findings indicate that motor cortex drives different muscle activation patterns via task-specific activity covariation. HIGHLIGHTSO_LIMice perform two forelimb tasks involving distinct antagonist muscle activity in a novel paradigm C_LIO_LIL5b motor cortical neurons are not organized by task-specific activity C_LIO_LIL5b motor cortical neurons do not encode muscle activity consistently across tasks C_LIO_LITask-specific muscle activity is driven by a change in motor cortical activity covariation C_LI eTOC BLURBWarriner et al. simultaneously measured muscle and motor cortical activity in mouse during antagonist forelimb muscle alternation and cocontraction, revealing that these distinct muscle activation patterns are not driven through consistent flexion and extension programs nor through the activity of discrete, task-specific neuronal subsets. Instead, distinct patterns involve task-specific changes in firing pattern covariation among layer 5b neurons, and corticospinal neurons in particular, which change their relationship to muscle activity across tasks.

neuroscience↗

bioRxiv2021

Unsupervised functional neurocartography of the Aplysia buccal ganglion

A major limitation of large-scale neuronal recordings is the difficulty in locating homologous neurons in different subjects, referred to as the "correspondence" issue. This issue stems, at least in part, from the lack of a unique feature that unequivocally identifies each neuron. One promising approach to this problem is the functional neurocartography framework developed by Frady et al. (2016), in which neurons are identified by a semisupervised machine learning algorithm using a combination of multiple selected features. Here, the framework was adapted to the buccal ganglia of Aplysia. Multiple features were derived from neuronal activity during motor pattern generation, responses to peripheral nerve stimulation, and the spatial properties of each cell. The feature set was optimized based on its potential usefulness in discriminating neurons from each other, and then used to match putatively homologous neurons across subjects with the functional neurocartography software. An alternative matching method based on a cyclic matching algorithm was also developed, which allows for unsupervised extraction of groups of neurons and automated selection of high-quality matches. This improvement enabled unsupervised implementation of the machine learning algorithm, thereby enhancing scalability of the analysis. This study paves the way for investigating the roles of both well-characterized and previously uncharacterized neurons in Aplysia, and helps to adapt the neurocartography framework to other systems.

neuroscience↗

bioRxiv2021

Neuronal population activity dynamics reveal a low-dimensional signature of operant learning

Learning engages a high-dimensional neuronal population space spanning multiple brain regions. We identified a low-dimensional signature associated with operant conditioning, a ubiquitous form of learning in which animals learn from the consequences of behavior. Using single-neuron resolution voltage imaging, we identified two low-dimensional motor modules in the neuronal population underlying Aplysia feeding. Our findings point to a temporal shift in module recruitment as the primary signature of operant learning.

neuroscience↗

bioRxiv2021

Diverse operant control of different motor cortex populations during learning

During motor learning, as well as during neuroprosthetic learning, animals learn to control motor cortex activity in order to generate behavior. Two different population of motor cortex neurons, intra-telencephalic (IT) and pyramidal tract (PT) neurons, convey the resulting cortical signals within and outside the telencephalon. Although a large amount of evidence demonstrates contrasting functional organization among both populations, it is unclear whether the brain can equally learn to control the activity of either class of motor cortex neurons. To answer this question, we used a Calcium imaging based brain-machine interface (CaBMI) and trained different groups of mice to modulate the activity of either IT or PT neurons in order to receive a reward. We found that animals learn to control PT neuron activity faster and better than IT neuron activity. Moreover, our findings show that the advantage of PT neurons is the result of characteristics inherent to this population as well as their local circuitry and cortical depth location. Taken together, our results suggest that motor cortex is optimized to control the activity of pyramidal track neurons, embedded deep in cortex, and relaying motor commands outside of the telencephalon.

neuroscience↗

bioRxiv2021

The brain uses invariant dynamics to generalize outputs across movements

It has been proposed that the nervous system has the capacity to generate a wide variety of movements because it re-uses some invariant code. Previous work has identified that dynamics of neural population activity are similar during different movements, where dynamics refer to how the instantaneous spatial pattern of population activity changes in time. Here we test whether invariant dynamics of neural populations are actually used to issue the commands that direct movement. Using a brain-machine interface that transformed rhesus macaques motor cortex activity into commands for a neuroprosthetic cursor, we discovered that the same command is issued with different neural activity patterns in different movements. However, these different patterns were predictable, as we found that the transitions between activity patterns are governed by the same dynamics across movements. These invariant dynamics are low-dimensional, and critically, they align with the brain-machine interface, so that they predict the specific component of neural activity that actually issues the next command. We introduce a model of optimal feedback control that shows that invariant dynamics can help transform movement feedback into commands, reducing the input that the neural population needs to control movement. Altogether our results demonstrate that invariant dynamics drive commands to control a variety of movements, and show how feedback can be integrated with invariant dynamics to issue generalizable commands.

neuroscience↗

bioRxiv2021

Transient dopamine neuron activity precedes and encodes the vigor of contralateral movements

Dopamine neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement vigor, and loss of these neurons leads to bradykinesia in Parkinsons disease. However, it remains unclear whether DANs encode a general motivation signal or modulate movement kinematics. We imaged activity of SNc DANs in mice trained in a novel operant task which relies on individual forelimb sequences. We uncovered that a similar proportion of SNc DANs increased their activity before ipsi- vs. contralateral sequences. However, the magnitude of this activity was higher for contralateral actions, and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-related DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal, and invigorate kinematic aspects of contralateral movements. TeaserTransient activity in substantia nigra compacta dopamine neurons encodes contralateral, but not ipsilateral action vigor.

neuroscience↗

bioRxiv2021

pyControl: Open source, Python based, hardware and software for controlling behavioural neuroscience experiments.

Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends we developed pyControl, a system of open source hardware and software for controlling behavioural experiments comprising; a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. ResourcesDocumentation: https://pycontrol.readthedocs.io Repositories: https://github.com/pyControl User support: https://groups.google.com/g/pycontrol

neuroscience↗

bioRxiv2020

Pyramidal tract neurons drive feed-forward excitation of striatum through cholinergic interneurons

Corticostriatal connectivity is central for many cognitive and motor processes, such as reinforcement or action initiation and invigoration. The cortical input to the striatum arises from two main cortical populations: intratelencephalic (IT) and pyramidal tract (PT) neurons. We uncovered a new feedforward excitatory circuit, supported by a polysynaptic motif from PT neurons to cholinergic interneurons (ChIs) to excitatory inputs, which runs in parallel to the canonical monosynaptic corticostriatal connection. This new motif conveys a delayed second phase of excitation to striatal spiny projection neurons (SPNs), through an acetylcholine-dependent glutamate release mechanism, resulting in biphasic corticostriatal signals. These biphasic signals are a hallmark of PT, but not IT, corticostriatal inputs, due to a stronger relative input from PT neurons to ChIs. These results uncover a novel feed-forward circuit mechanism by which PT activity differentially gates excitatory inputs to the striatum, with potential implications for behavior, plasticity and learning. HighlightsO_LIPT, but not IT, corticostriatal inputs convey biphasic excitation to SPNs via a disynaptic circuit involving striatal ChIs. C_LIO_LIPT neurons recruit ChIs more efficiently than IT neurons due to a stronger relative input to ChIs. C_LIO_LIThe second phase of SPN excitation is mediated by nicotinic receptors at long-range glutamatergic axons in the striatum. C_LIO_LISuprathreshold depolarizations of SPNs by PT inputs depend on ChI[->]SPN excitation and result in delayed spiking. C_LI

neuroscience↗

bioRxiv2020

Corticospinal neurons encode complex motor signals that are broadcast to dichotomous striatal circuits

Sensorimotor cortex controls movement in part through direct projections to the spinal cord. Here we show that these corticospinal neurons (CSNs) possess axon collaterals that innervate many supraspinal brain regions critical for motor control, most prominently the main input to the basal ganglia, the striatum. Corticospinal neurons that innervate the striatum form more synapses on D1-than D2-striatal projection neurons (SPNs). This biased innervation strategy corresponds to functionally distinct patterns of termination in spinal cord. CSNs are strongly driven during a striatum-dependent sequential forelimb behavior, and often represent high level movement features that are not linearly related to kinematic output. Copies of these activity patterns are relayed in a balanced fashion to both D1 and D2 projection pathways. These results reveal a circuit logic by which motor cortex corticospinal neurons relay both kinematic-related and unrelated signals to distinct striatal and spinal cord pathways, where postsynaptic connectivity ultimately dictates motor specificity. HighlightsO_LICorticospinal neurons send axon collaterals most abundantly to the striatum C_LIO_LIBiases in striatal innervation correspond to biases in spinal innervation C_LIO_LICSNs represent complex movement sequence information C_LIO_LICorollary motor sequence signals are relayed to both striatal projection pathways C_LI eTOC BlurbNelson, A. et al. detail the organization of corticospinal neurons and their coordinated cell type-specific targets in the dorsolateral striatum and spinal cord. Corticospinal neurons encode both kinematic-related and unrelated signals during motor sequences, and relay this information in a balanced fashion to dichotomous striatal pathways.

neuroscience↗