Browsing by Subject "Striatum"

Many of the skills we value most as humans, such as speech and learning to play musical instruments, are learned in the absence of external reinforcement. However, the model systems most commonly used to study motor learning employ learning paradigms in which animals perform behaviors in response to external rewards or punishments. Here I use the zebra finch, an Australian songbird that can learn its song as a juvenile in the absence of external reinforcement as well as modify its song in response to external cues as an adult, to study the circuit mechanisms underlying both internally and externally reinforced forms of learning. Using a combination of intersectional genetic and microdialysis techniques, I show that a striatonigral pathway and its downstream effectors, namely D1-type dopamine receptors, are necessary for both internally reinforced juvenile learning and externally reinforced adult learning, as wells as for song modification in response to social cues or to deafening. In addition, I employ optogenetic stimulation during singing to demonstrate that this striatonigral projection is sufficient to drive learning. Interestingly, I find that neither the striatonigral pathway nor D1-type dopamine receptors are necessary for recovery of pitch after externally driven pitch learning. In all, I establish that a common mechanism underlies both internally and externally reinforced vocal learning.

Humans and animals have remarkable capabilities in keeping time and using time as a guide to orient their learning and decision making. Psychophysical models of timing and time perception have been proposed for decades and have received behavioral, anatomical and pharmacological data support. However, despite numerous studies that aimed at delineating the neural underpinnings of interval timing, a complete picture of the neurobiological network of timing in the seconds-to-minutes range remains elusive. Based on classical interval timing protocols and proposing a Timing, Immersive Memory and Emotional Regulation (TIMER) test battery, the author investigates the contributions of the dorsal and ventral hippocampus as well as the dorsolateral and the dorsomedial striatum to interval timing by comparing timing performances in mice after they received cytotoxic lesions in the corresponding brain regions. On the other hand, a timing-based theoretical framework for the emergence of conscious experience that is closely related to the function of the claustrum is proposed so as to serve both biological guidance and the research and evolution of “strong” artificial intelligence. Finally, a new “Double Saturation Model of Interval Timing” that integrates the direct- and indirect- pathways of striatum is proposed to explain the set of empirical findings.

The striatum is a key brain region for learning and producing movement. Little is known about the molecular mechanisms in the early postnatal period that regulate how medium spiny neurons (MSNs), the predominant cell type in this region, mature. Using electrophysiology in acute brain slices in combination with pharmacological and genetic manipulations of the metabotropic glutamate receptor, mGluR5, I present evidence that mGluR5 may regulate synapse unsilencing. This developmental effect of mGluR5 signaling appears to be modulated by other processes, which I was unable to fully elucidate. However, activation of mGluR5 signaling later in postnatal development is sufficient to reduce excitatory glutamatergic transmission. These data indicate that mGluR5 has important roles in regulating striatal transmission that may be differentially regulated over development.

Habit formation is a behavioral adaptation that automates routine actions. This automation preserves cognitive resources that would otherwise be used to monitor action-outcome relationships. The dorsolateral striatum (DLS), which serves as the brain’s conduit into the basal ganglia, has been implicated in habit formation. However, it was not known whether and how the local DLS circuitry adapts to facilitate habitual behavior. By imaging DLS input-output computations of mice trained in a lever pressing task, I identified pathway-specific features of DLS output that strongly predicted the expression and suppression of habitual behavior. These results demonstrated that DLS actively contributes to the habit memory. To understand how these circuit-level adaptations arise, I then performed a series of ex vivo and in vivo experiments probing the local striatal microcircuitry in the context of habits. I found that a single class of interneuron, the striatal fast-spiking interneuron (FSI), was responsible for these habit-predictive changes in DLS output. I further found that FSIs undergo experience-dependent plasticity with habit formation and that their activity in DLS is required for the expression of habitual behavior. Surprisingly, FSIs also appeared to paradoxically excite physiologically distinct subsets of projection neurons in vivo. Taken together, this body of work outlines a circuit- and microcircuit-level mechanism whereby DLS provides a necessary contribution to the neurobiological underpinnings of habit.

The striatum is the input nucleus of basal ganglia, a group of subcortical nuclei that includes the striatum, globus pallidus, subthalamic nucleus, and substantia nigra. These brain regions have been implicated in control and coordination of motor planning and action selection. Especially, the dorsal striatum (sensorimotor striatum) is important for movement control. Movement is a change in body configuration or posture. A key feature of voluntary movements is that we can arbitrarily vary movement velocity, defined as the rate of change in body configurations. Despite extensive studies that have attempted to elucidate the relationship between neurons in the dorsal striatum and movement, the mechanism of how striatal activity in the dorsal striatum contributes to movement velocity remains unclear. One reason is that traditional experimental designs of the basal ganglia have either considered actions as discrete events or neglected to measure movements with the precise spatial and temporal resolutions required to understand the neural substrates of behavior. For example, many studies have used movement initiation as a behavioral variable, but it is unclear how fast the animal moved, in what direction, or what effectors were used. The following experiments were designed to investigate the role of striatal neurons in controlling movement velocity in mice. The first set of experiments (Chapter 2) examined the relationship between striatal activity and movement velocity. Using wireless in vivo electrophysiology recording and video tracking, we recorded single‐unit activity from spiny projection neurons (SPNs) and fast‐spiking interneurons (FSIs) while monitoring the movements of mice. In Experiment 1, we trained animals to generate movements toward the waterspout by water‐depriving them and giving them periodic cued sucrose rewards. We found high correlations between neural activity and direction-specific movement velocity. This correlation was found in both putative SPNs and FSIs. In Experiment 2, to rule out the possibility that the observed correlations were due to reward expectancy, we repeated the same procedure but added a condition in which sucrose delivery was replaced by an aversive air puff stimulus. The air puff generated avoidance movements that were clearly different from movements on rewarded trials. However, the same neurons that showed velocity correlation on reward trials exhibited a similar correlation on air puff trials. These experiments show that the firing rate of striatal neurons reflects direction-specific movement velocity regardless of the valence of the outcome. The second set of experiments (Chapter 3) examined a striatal microcircuit underlying pursuing behavior. The SPNs and FSIs in the striatum compose a striatal microcircuit that provides a feedforward inhibition circuit in which glutamatergic inputs excite the FSIs that then inhibit the SPNs. By using 3D motion capture, in vivo electrophysiology and calcium imaging, we recorded neural activity from SPNs and FSIs while precisely monitoring mice during a task where they are trained to follow a moving target to earn a reward. We showed that, in the sensorimotor striatum, parvalbumin-positive (PV+) FSIs can represent the distance between self and target during pursuit behavior, while SPNs can represent movement velocity. We found that PV+ FSIs were shown to regulate velocity-related SPNs during pursuit, so that movement velocity is continuously regulated by distance to target. Moreover, bidirectional manipulation of PV+ FSIs can selectively disrupt pursuit behavior by increasing or decreasing the distance. These experiments reveal a key role of the microcircuit between FSIs and SPNs in pursuit behavior and elucidate how this circuit implements the distance to velocity transformation by formalizing the explicit computation used. The third set of experiments (Chapter 4) examined the role of direct and indirect pathways in velocity control during switching behavior in which animals were trained on a task with two different targets. Mice had to approach one target, then switch to another target to earn a reward. Direct pathway (striatonigral) neurons express D1 receptors and project to the substantia nigra pars reticulata (SNr) and other BG output nuclei. Indirect pathway (striatopallidal) neurons express D2 and A2A receptors and project primarily to the globus pallidus. Using 3D motion capture and in vivo calcium imaging, we recorded neural activity from direct and indirect pathway SPNs while monitoring mice’s behavior as they switched between the two targets. We showed that the direct pathway is responsible for increase of velocity whereas the indirect pathway is involved in decrease of velocity. Moreover, bidirectional manipulation of direct and indirect pathways can increase and decrease the movement velocity causing bidirectional errors. These experiments reveal the opposite role in velocity control between direct and indirect pathways during switching behavior and elucidate how these pathways contribute to control of movement velocity. Taken together, these experiments demonstrate that not only is the striatum involved in the control of movements, they provide the mechanism of how striatal microcircuits in the dorsal striatum contributes to movement velocity.

The ultimate goal of the nervous systems of all animals is conceptually simple: Manipulate the external environment to maximize one's own survival and reproduction. The myriad means animals employ in pursuit of this goal are astoundingly complex, but constrained by common factors. For example, to ensure survival, all animals must acquire the necessary nutrients to sustain metabolism. Similarly, social interaction of some form is necessary for mating and reproduction. For some animals, the required social interaction goes far beyond that necessary for mating. Humans and many other primates exist in complex social environments, the navigation of which are essential for adaptive behavior. This dissertation is concerned with processes of transforming sensory stimuli regarding both nutritive and social information into motor commands pursuant to the goals of survival and reproduction. Specifically, this dissertation deals with these processes in the rhesus macaque. Using a task in which monkeys make decisions simultaneously weighing outcomes of fruit juices and images of familiar conspecifics, I have examined the neurophysiology of social and nutritive factors as they contribute to choice behavior; with the ultimate goal of understanding how these disparate factors are weighed against each other and combined to produce coherent motor commands that result in adaptive social interactions and the successful procurement of resources. I began my investigation in the lateral intraparietal cortex, a well-studied area of the primate brain implicated in visual attention, oculomotor planning and control, and reward processing. My findings indicate the lateral intraparietal cortex represents social and nutritive reward information in a common neural currency. That is, the summed value of social and nutritive outcomes is proportional to the firing rates of parietal neurons. I continued my investigation in the striatum, a large and functionally diverse subcortical nuclei implicated in motor processing, reward processing and learning. Here I find a different pattern of results. Striatal neurons generally encoded information about either social outcome or juice rewards, but not both, with a medial or lateral bias in the location of social or juice information encoding neurons, respectively. In further contrast to the lateral intraparietal cortex, the firing rates of striatal neurons coding social and nutritive outcome information is heterogeneous and not directly related to the value of the outcome. This dissertation represents a few incremental steps toward understanding how social information and the drive toward social interaction are incorporated with other motivators to influence behavior. Understanding this process is a necessary step for elucidating, treating, and preventing pathologies