A Direct Path to Action Initiation
Authors: Christopher H. Donahue, Anatol C. Kreitzer
Journal: Neuron (2015)

In this issue of Neuron, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar provide the clearest evidence to date that information is differentially encoded in the direct and indirect pathways of the striatum. The results support the classical notion that the direct pathway plays a critical role in initiating actions. In this issue of Neuron, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar provide the clearest evidence to date that information is differentially encoded in the direct and indirect pathways of the striatum. The results support the classical notion that the direct pathway plays a critical role in initiating actions. A fundamental challenge that all animals face is how to interpret incoming sensory information and transform it into an appropriate motor response. In this issue of Neuron, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar provide valuable insight into how circuitry in a nucleus of the basal ganglia known as the striatum, plays a critical role in initiating these motor responses. The striatum serves as the main input nucleus of the basal ganglia and contains two intermingled classes of GABAergic projection neurons that exert opposing effects on downstream structures. The direct-pathway spiny projection neurons (dSPNs) express D1 dopamine receptors and project directly to the substantia nigra pars reticulata (SNr), the main output nucleus of the basal ganglia. The indirect-pathway projection neurons (iSPNs) express D2 receptors and form the beginning of a circuit that indirectly projects to the SNr via the globus pallidus external segment (GPe). The relative balance of activity in these two pathways is thought to play a central role in motor control and action initiation. According to classical models of basal ganglia function (Albin et al., 1989Albin R.L. Young A.B. Penney J.B. Trends Neurosci. 1989; 12: 366-375Abstract Full Text PDF PubMed Scopus (4047) Google Scholar, DeLong, 1990DeLong M.R. Trends Neurosci. 1990; 13: 281-285Abstract Full Text PDF PubMed Scopus (3022) Google Scholar), dSPNs are part of a "go" pathway that facilitates movement while iSPNs are part of a "no go" pathway that suppresses undesired movements. These neurons receive a robust dopaminergic projection from the substantia nigra pars compacta (SNc). Dopamine is theorized to have opposing effects on the balance of activity in the direct and indirect pathways through its differential action on D1 and D2 receptors (Surmeier et al., 2007Surmeier D.J. Ding J. Day M. Wang Z. Shen W. Trends Neurosci. 2007; 30: 228-235Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar). This has long served as a model for thinking about the debilitating effects observed in Parkinson's disease, where the loss of dopaminergic input leads to a disproportionate increase in indirect pathway activity and the consequent inability to generate movement. Experimental validation of the classical model in awake behaving animals was not possible through the use of traditional methods such as extracellular recording and electrical stimulation, since dSPNs and iSPNs are intermixed in the striatum and are electrophysiologically indistinguishable. However, with the development of bacterial artificial chromosome (BAC) transgenic mice and optogenetic methods, it finally became possible to test the classical model's predictions about the role of direct and indirect pathway control of movement. These initial studies found that selective stimulation of dSPNs in the striatum of freely moving mice leads to a substantial increase in movement, while activation of the indirect pathway leads to a strong suppression of movement (Kravitz et al., 2010Kravitz A.V. Freeze B.S. Parker P.R.L. Kay K. Thwin M.T. Deisseroth K. Kreitzer A.C. Nature. 2010; 466: 622-626Crossref PubMed Scopus (1224) Google Scholar). Subsequent studies using optogenetic stimulation have largely continued to support the basic predictions of the classical model. In contrast to the clear behavioral effects that have been observed with pathway-specific optogenetic stimulation, we know very little about what kind of information is encoded in the neural activity of dSPNs and iSPNs. One recent recording study has challenged simple versions of the classical model by showing robust co-activation of striatal dSPNs and iSPNs during movements (Cui et al., 2013Cui G. Jun S.B. Jin X. Pham M.D. Vogel S.S. Lovinger D.M. Costa R.M. Nature. 2013; 494: 238-242Crossref PubMed Scopus (750) Google Scholar). Through the use of a genetically encoded calcium indicator, the authors measured bulk population activity in either dSPNs or iSPNs while mice performed a simple operant task. This recording method is advantageous in the sense that it can be easily used to image deep structures such as the striatum in freely moving animals, but it lacks the temporal resolution of electrophysiological methods. According to some versions of the classical model, one prediction is that dSPNs would be more active during movement, whereas iSPNs would be more active during periods of rest. Instead, the authors found that both subpopulations were more active when the animals initiated actions, although subtle differences in spiking between the two populations could not be resolved. While these results seem to pose a significant challenge to the simplest interpretation of the classical model, they are still consistent with the idea that dSPNs initiate appropriate motor responses while iSPNs are simultaneously active to suppress competing responses (Mink, 1996Mink J.W. Prog. Neurobiol. 1996; 50: 381-425Crossref PubMed Scopus (1833) Google Scholar). A more recent electrophysiological study has reconfirmed that dSPNs and iSPNs are both active during action initiation but may differ in how they encode information related to action sequences (Jin et al., 2014Jin X. Tecuapetla F. Costa R.M. Nat. Neurosci. 2014; 17: 423-430Crossref PubMed Scopus (293) Google Scholar). While these recording studies point toward a more nuanced view of how the direct and indirect pathways might contribute to action initiation, it is still unclear how to reconcile these results with the previous optogenetic findings, since there exist such few data about how dSPNs and iSPNs respond in behaving animals. In this issue, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar provide the best evidence to date for pathway-specific differences in neural activity in striatal projection neurons during goal-directed behavior. To achieve this, they obtained whole-cell recordings in head-fixed mice that were trained on a task that required them to perform a simple sensorimotor transformation. The whole-cell recording technique, while low yield and technically challenging, proved to be critical to their success. One of the key physiological features of SPNs is their low baseline firing rates. Through the use of this technique, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar gained access to the rich subthreshold membrane potential dynamics that underlie action potential generation and could therefore define with fine temporal precision any potential differences between dSPN and iSPN neural activity that may have been missed with the use of other methods. The mice were trained to lick a reward spout in response to a single whisker deflection (Sachidhanandam et al., 2013Sachidhanandam S. Sreenivasan V. Kyriakatos A. Kremer Y. Petersen C.C.H. Nat. Neurosci. 2013; 16: 1671-1677Crossref PubMed Scopus (226) Google Scholar). After the animals were well-trained, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar recorded from cells in the dorsolateral striatum that are known to receive direct input from primary somatosensory cortex (Alexander et al., 1986Alexander G.E. DeLong M.R. Strick P.L. Annu. Rev. Neurosci. 1986; 9: 357-381Crossref PubMed Scopus (6726) Google Scholar) and were therefore likely to encode information important to the sensorimotor transformation. Following successful completion of the task, the authors were later able to determine whether they had recorded from a dSPN or iSPN through post hoc histology. These recordings unveiled several interesting characteristics of SPN activity. First, neuronal responses in both pathways consisted of two distinct phases: a fast transient depolarization that immediately followed whisker detection and a slower sustained depolarization that occurred afterward. Activity was compared during successful trials ("hits") where whisker deflection correctly led to a lick response and during unsuccessful trials ("misses") where the animals failed to lick. Across the entire population of recorded SPNs, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar found that the depolarizing response in both the transient and sustained phase of the response was larger in "hit" trials, regardless of neuronal subtype. This indicated that neuronal activity in SPNs predicted behavioral performance and could potentially play an important role in contributing to correct behavior in their task. When Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar separated the responses according to neuronal subtype, they found that dSPNs were solely responsible for the fast transient phase of the response, while this was completely absent from the iSPN responses. This is consistent with a recent anatomical tracing study that revealed preferential innervation of dMSNs by sensory and limbic afferents (Wall et al., 2013Wall N.R. De La Parra M. Callaway E.M. Kreitzer A.C. Neuron. 2013; 79: 347-360Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar). During the late-phase sustained responses, dMSNs and iMSNs were indistinguishable from one another. These results provided initial correlative evidence that dSPNs in the direct pathway play a specific role in transforming sensory responses into behavioral output. To examine whether there was a causal relationship, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar turned to optogenetics. Mice were trained to perform the same task, but on a small fraction of trials, they received laser stimulation instead of a whisker deflection. They found that brief excitation of the dSPN population could mimic whisker deflection by evoking a licking response. In contrast, excitation of the iSPN population did not cause the animals to lick. Together, the recording and optogenetic results indicate that the direct pathway plays a specific role in initiating the "go" response. These results provide further evidence in favor of the classical model and help resolve outstanding questions regarding the seemingly conflicting literature surrounding stimulation and recording in the striatum. These results suggest several interesting avenues for future research. In a previous study from the same lab using the same behavioral paradigm, it was found that neuronal responses in primary somatosensory cortex (S1) showed no differences between "hit" and "miss" trials during the early transient response (Sachidhanandam et al., 2013Sachidhanandam S. Sreenivasan V. Kyriakatos A. Kremer Y. Petersen C.C.H. Nat. Neurosci. 2013; 16: 1671-1677Crossref PubMed Scopus (226) Google Scholar). In contrast, Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar found that dSPNs displayed a significantly larger response on "hit" trials. As the authors note, this brings up the question of whether the enhanced responses in the striatum arise from differential inputs or whether they are internally generated within the striatum. Given the robust dopaminergic projections from SNc to the striatum and the bidirectional dopamine-dependent plasticity that is hypothesized to drive learning in the striatum (Surmeier et al., 2007Surmeier D.J. Ding J. Day M. Wang Z. Shen W. Trends Neurosci. 2007; 30: 228-235Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar, Shen et al., 2008Shen W. Flajolet M. Greengard P. Surmeier D.J. Science. 2008; 321: 848-851Crossref PubMed Scopus (854) Google Scholar), it is possible that delivery of reward during the initial learning of the task could have led to dopamine-dependent potentiation of task-relevant corticostriatal inputs onto dSPNs and depression onto iSPNs to create the response properties that Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar observe. While much of the focus on striatal circuit function is dedicated to motor control and execution, the direct and indirect pathways have also been shown to play a selective role in learning from reward and punishment, respectively (Frank et al., 2004Frank M.J. Seeberger L.C. O'reilly R.C. Science. 2004; 306: 1940-1943Crossref PubMed Scopus (1376) Google Scholar, Kravitz et al., 2012Kravitz A.V. Tye L.D. Kreitzer A.C. Nat. Neurosci. 2012; 15: 816-818Crossref PubMed Scopus (638) Google Scholar, Tai et al., 2012Tai L.H. Lee A.M. Benavidez N. Bonci A. Wilbrecht L. Nat. Neurosci. 2012; 15: 1281-1289Crossref PubMed Scopus (231) Google Scholar). The task used in Sippy et al., 2015Sippy T. Lapray D. Crochet S. Petersen C.C.H. Neuron. 2015; 88 (this issue): 298-305Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar examined pathway specific responses to a single well-learned sensorimotor transformation. It would be particularly interesting to record from identified subpopulations during tasks where the animals must dynamically adjust their behavior in response to various levels of reward and/or punishment. Such dynamic learning tasks may do a much better job of revealing functional differences in these striatal subpopulations. As more sophisticated decision-making behaviors are now becoming possible in mice, many exciting questions of how the direct and indirect pathways encode information beyond simple motor-related parameters are finally becoming accessible. Cell-Type-Specific Sensorimotor Processing in Striatal Projection Neurons during Goal-Directed BehaviorSippy et al.NeuronOctober 1, 2015In BriefSippy et al. measure cell-type-specific membrane potential dynamics in the striatum of head-restrained mice performing a simple goal-directed sensorimotor transformation. Their results are consistent with direct pathway striatonigral neurons delivering a fast "go" signal for action initiation. Full-Text PDF Open Access