Browsing by Subject "Basal ganglia"
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Item Open Access Basal Ganglia Regulation of Motivated Behaviors(2015) Rossi, Mark AllenFinding and consuming food and water are among the most critical functions for an animal's survival. Food seeking (e.g., exploration and approach) and consummatory (e.g., licking, chewing, swallowing) behaviors are usually highly controlled, resulting in stable food intake, body mass, and fat stores in humans and laboratory animals. These variables are thought to be governed by homeostatic control systems that closely regulate many aspects of feeding behavior. However, the homeostatic mechanisms underlying these processes are often disrupted in humans, resulting in either hyperphagia or hypophagia. Despite many decades of investigations into the regulatory circuits of animals and humans, the neural circuits that underlie voluntary feeding are unclear. There have been considerable advances into understanding how the brain is able to broadly regulate food consumption (e.g., the role of circulating hormones on food intake and body weight). As much work has focused on hypothalamic mechanisms, relatively little is known about how other neural systems contribute to specific aspects of food seeking and consumption.
The basal ganglia have been implicated in many aspects of motivated behavior including appetitive and consummatory processes. However, the precise role that basal ganglia pathways play in these motivated behaviors remain largely unknown. One reason for this is that the basal ganglia are functionally and anatomically heterogeneous, with distinct functional circuit elements being embedded within overlapping tissue. Until recently, tools permitting identification and manipulation of molecularly defined neuron populations were unavailable.
The following experiments were designed to assess the role of the basal ganglia in regulating appetitive and consummatory behavior in mice. The first experiment (Chapter 2) examines the relationship between neural activity in the substantia nigra¬, a¬ major output nucleus of the basal ganglia, and an animal's motivational state. Both dopaminergic and GABAergic neurons show bursts of action potentials in response to a cue that predicts a food reward in hungry mice. The magnitude of this burst response is bidirectionally modulated by the animal's motivational state. When mice are sated prior to testing, or when no pellets can be consumed, both motivational state and bidirectional modulation of the cue response are unchanging.
The second set of experiments (Chapter 3 and 4) utilizes a mouse model of hyperdopaminergia: Dopamine transporter knockout mice. These mice have persistently elevated synaptic dopamine. Consistent with a role of dopamine in motivation, hyperdopaminergic mice exhibit enhanced food seeking behavior that is dissociable from general hyperactivity. Lentiviral restoration of the dopamine transporter into either the dorsolateral striatum or the nucleus accumbens, but not the dorsomedial striatum, is sufficient to selectively reduce excessive food seeking. The dopamine transporter knockout model of hyperdopaminergia was then used to test the role of dopamine in consummatory processes, specifically, licking for sucrose solution. Hyperdopaminergic mice have higher rates of licking, which was due to increased perseveration of licking in a bout. By contrast, they have increased individual lick durations, and reduced inter-lick-intervals. During extinction, both knockout and control mice transiently increase variability in lick pattern generation while reducing licking rate. Yet they show very different behavioral patterns. Control mice gradually increase lick duration as well as variability in extinction. By contrast, dopamine transporter knockout mice exhibited more immediate (within 10 licks) adjustments--an immediate increase in lick duration variability, as well as more rapid extinction. These results suggest that the level of dopamine can modulate the persistence and pattern generation of a highly stereotyped consummatory behavior like licking, as well as new learning in response to changes in environmental feedback.
The final set of experiments was designed to test the relationship between consummatory behavior and the activity of GABAergic basal ganglia output neurons projecting from the substantia nigra pars reticulata to the superior colliculus, an area that has been implicated in regulating orofacial behavior. Electrophysiological recording from mice during voluntary drinking showed that activity of GABAergic output neurons of the substantia nigra pars reticulata reflect the microstructure of consummatory licking. These neurons exhibit oscillatory bursts of activity, which are usually in phase with the lick cycle, peaking near the time of tongue protrusion. Dopaminergic neurons, in contrast, did not reflect lick microstructure, but instead signaled the boundaries of a bout of licking. Neurons located in the lateral part of the superior colliculus, a region that receives direct input from GABAergic projection neurons in the substantia nigra pars reticulata, also reflected the microstructure of licking with rhythmic oscillations. These neurons, however, showed a generally opposing pattern of activity relative to the substantia nigra neurons, pausing their firing when the tongue is extended. To test whether perturbation of the nigrotectal pathway could influence licking behavior, channelrhodopsin-2 was selectively expressed in GABAergic neurons of the substantia nigra and the axon terminals within the superior colliculus were targeted with optic fibers. Activation of nigrotectal neurons disrupted licking in a frequency-dependent manner. Using optrode recordings, I demonstrate that nigrotectal activation inhibits neurons in the superior colliculus to disrupt the pattern of licking.
Taken together, these results demonstrate that the basal ganglia are involved in both appetitive and consummatory behaviors. The present data argue for a role of striatonigral dopamine in regulating general appetitive responding: persistence of food-seeking. Nigraltectal GABA neurons appear to be critical for consummatory orofacial motor output.
Item Open Access Mechanisms of Deep Brain Stimulation for the Treatment of Parkinson's Disease: Evidence from Experimental and Computational Studies(2012) So, Rosa Qi YueDeep brain stimulation (DBS) is used to treat the motor symptoms of advanced Parkinson's disease (PD). Although this therapy has been widely applied, the mechanisms of action underlying its effectiveness remain unclear. The goal of this dissertation was to investigate the mechanisms underlying the effectiveness of subthalamic nucleus (STN) DBS by quantifying changes in neuronal activity in the basal ganglia during both effective and ineffective DBS.
Two different approaches were adopted in this study. The first approach was the unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model. Using this animal model, we developed behavioral tests that were used to quantify the effectiveness of DBS with various frequencies and temporal patterns. These changes in behavior were correlated with changes in the activity of multiple single neurons recorded from the globus pallidus externa (GPe) and substantia nigra reticulata (SNr). The second approach was a computational model of the basal ganglia-thalamic network. The output of the model was quantified using an error index that measured the fidelity of transmission of information in model thalamic neurons. We quantified changes in error index as well as neural activity within the model GPe and globus pallidus interna (GPi, equivalent to the SNr in rats).
Using these two approaches, we first quantified the effects of different frequencies of STN DBS. High frequency stimulation was more effective than low frequency stimulation at reducing motor symptoms in the rat, as well as improving the error index of the computational model. In both the GPe and SNr/GPi from the rat and computational model, pathological low frequency oscillations were present. These low frequency oscillations were suppressed during effective high frequency DBS but not low frequency DBS. Furthermore, effective high frequency DBS generated oscillations in neural firing at the same frequency of stimulation. Such changes in neuronal firing patterns were independent of changes in firing rates.
Next, we investigated the effects of different temporal patterns of high frequency stimulation. Stimulus trains with the same number of pulses per second but different coefficients of variation (CVs) were delivered to the PD rat as well as PD model. 130 Hz regular DBS was more effective than irregular DBS at alleviating motor symptoms of the PD rat and improving error index in the computational model. However, the most irregular stimulation pattern was still more effective than low frequency stimulation. All patterns of DBS were able to suppress the pathological low frequency oscillations present in the GPe and SNr/GPi, but only 130 Hz stimulation increased high frequency 130 Hz oscillations. Therefore, the suppression of pathological low frequency neural oscillations was necessary but not sufficient to produce the maximum benefits of DBS.
The effectiveness of regular high frequency STN DBS was associated with a decrease in pathological low frequency oscillations and an increase in high frequency oscillations. These observations indicate that the effects of DBS are not only mediated by changes in firing rate, but also involve changes in neuronal firing patterns within the basal ganglia. The shift in neural oscillations from low to high frequency during effective STN DBS suggests that high frequency regular DBS suppresses pathological firing by entraining neurons to the stimulus pulses.
Therefore, results from this dissertation support the hypothesis that the underlying mechanism of effective DBS is its ability to entrain and regularize neuronal firing, therefore disrupting pathological patterns of activity within the basal ganglia.
Item Open Access Neural Dynamics in the Basal Ganglia Underlying Birdsong Practice and Performance(2021) Singh Alvarado, JonnathanSkilled movements are typically more variable during practice, promoting exploration, yet highly stereotyped during performance, favoring exploitation. How neurons encode and dynamically regulate motor variability across practice and performance states remains unknown. Songbirds sing more variable songs when practicing alone and highly stereotyped songs when performing to a female, providing a powerful system to explore how neural ensembles regulate motor variability. Here, I used this system to identify neural mechanisms underlying practice and performance. First, I used deep brain imaging techniques to demonstrate that spiny neurons (SNs) in the basal ganglia (BG) encode vocal variability during solo practice, and that SN activity is strongly suppressed to enable stereotyped song performance towards a female. Second, I showed that optogenetically inhibiting SNs reduces pitch variability to female-directed levels. Third, I collaborated with Dr. John Pearson’s lab to uncover a coding scheme whereby specific patterns of SN activity map onto distinct spectral variants of syllables during vocal practice. Lastly, I use photometry, anatomical tracing, molecular profiling, and ex vivo physiology to establish that adrenergic signaling in the BG regulates vocal variability by directly suppressing SN activity. I conclude that SN ensembles encode and drive vocal exploration during practice, and the social context-dependent noradrenergic regulation of SN activity enables stereotyped and highly precise vocal performance.
Item Open Access Striatal circuit and microcircuit mechanisms for habitual behavior(2017) O'Hare, JustinHabit 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.
Item Open Access The Role of the Substantia Nigra in Goal Directed Behavior(2015) Barter, Joseph WilliamAnimals must continuously move through the environment in pursuit of the goals required to maintain homeostasis. In vertebrates, this is accomplished through an ever-changing pattern of muscle contraction in a multipurpose body, and coordinated by a hierarchy of neural circuits acting in parallel. At the lower levels of this hierarchy, spinal circuits control muscle force and length. One level above that, brainstem, midbrain and cortical circuits control various aspects of body configuration as well as a number of self-contained motor functions including locomotion and orientation. A still-higher level of organization is controlled by the basal ganglia, a set of subcortical nuclei that appear to be responsible for continuously orchestrating the extent and direction of various motor programs and body configurations for the sake of controlling a still higher level of perceptual variable, such as proximity to food. In this way, the basal ganglia orchestrate the performance of motor functions to achieve a single goal in the same way that a conductor orchestrates the performance of musicians in a symphony to achieve a single song.
Despite the continuous and graded nature of animal behavior, researchers have traditionally studied the basal ganglia in the context of highly controlled experimental tasks or neglected to record continuous measures of behavioral outputs. To address this gap, the following experiments were designed investigate role of the basal ganglia in continuously modulating unconstrained goal directed movements. In the first set of experiments (chapter 2), mice stood on a small covered perch which was continuously tipped left and right along the roll plane while neural activity was recorded wirelessly. During each recording session, mice were exposed to slow and fast speeds of postural disturbance. Pressure pads were mounted in the left and right floor of the perch to monitor mouse movement. In both putative dopamine and GABA neurons, we found two basic patterns of neural activity; one class of cell increased firing with tip to the left and decreased with tip to the right while the other class decreased firing with tip to the left and increased with tip to right. This correlation between neural firing rate and instantaneous postural disturbance is continuous and very high. The correlation is seen for both slow and fast disturbances. The majority of cells recorded fell into one of these two categories. Pressure pad readout, as expected, revealed paw forces on the left pad to increase with tilt to the left and decrease with tilt to the right while the opposite pattern was observed on the right pad. These results show continuous and graded modulation of activity in the substantia nigra during performance of an ongoing motor task and suggest that BG outputs, rather than monolithically disinhibiting brainstem motor structures, instead coordinate behavior by continuously specifying desired states of lower systems.
In the second set of experiments (chapter 3), we employed continuous motion tracking of the head in parallel with neural recording from the substantia nigra pars reticulata during a simple goal-directed task. In this study, mice were water deprived and then positioned on a perch equipped with a movable drinking spout. During each session, mice performed a simple reward-guided task in which sucrose solution was delivered in small quantities after the presentation a cue. The purpose of this task was to elicit voluntary head movements and to investigate the relationship between these continuous movements and the activity of GABA output neurons. A typical reward-directed behavior involved the movement of the whole head and body to collect the sucrose solution following its delivery. However, movements during each individual trial were unique. For all movements, the majority of GABA cells were found to either positively or negatively correlate with either X or Y axis head position vector components. These correlations were very high, and not due to averaging artifacts as trial-by-trial correlation between movement and neural activity can be clearly observed. These correlations were also independent of the presence of a reward. These data show for the first time a continuous and quantitative relationship between basal ganglia output and body posture. It is hypothesized that these signals represent reference signals sent to downstream postural and orientation controllers. In this case a baseline level of GABA activity would represent neutral reference position, and changes in activity above and below this level represent increased or decreased reference positions.
In the third set of experiments (chapter 4), we recorded from dopamine neurons in the substantia nigra pars compacta during the same task as in chapter 3. The purpose of this task was to investigate the correlation between dopamine activity and movement kinematics during goal-directed behavior. Animals were found to produce movements at the onset of the cue and also at reward delivery. Dopamine-classified cells show phasic firing or pausing at the onset of each of these movements. When compared to head movement kinematics, these patterns of neural activity correlate highly with different vector components of head acceleration and velocity; up, down, left and right. Importantly, these correlations are continuous and exist throughout the entire recording session. These correlations are also independent of the presence of reward. To test the ‘causality’ of these observed patterns, we also employed optogenetics to stimulate substantia nigra dopamine neurons expressing channel rhodopsin 2 (Chr2) while head movements were recorded and quantified. We found that stimulation of ChR2-expressing animals could elicit head movement while stimulation of control animals had no effect. Combined, these data suggest that dopamine is responsible for controlling the velocity of transitions between different body postures.