Cell assembly dynamics of sparsely-connected inhibitory networks: a simple model for the collective activity of striatal projection neurons

Striatal projection neurons form a sparsely-connected inhibitory network, and this arrangement may be essential for the appropriate temporal organization of behavior. Here we show that a simplified, sparse inhibitory network of Leaky-Integrate-and-Fire neurons can reproduce some key features of striatal population activity, as observed in brain slices [Carrillo-Reid et al., J. Neurophysiology 99 (2008) 1435{1450]. In particular we develop a new metric to determine the conditions under which sparse inhibitory networks form anti-correlated cell assemblies with time-varying activity of individual cells. We found that under these conditions the network displays an input-specific sequence of cell assembly switching, that effectively discriminates similar inputs. Our results support the proposal [Ponzi and Wickens, PLoS Comp Biol 9 (2013) e1002954] that GABAergic connections between striatal projection neurons allow stimulus-selective, temporally-extended sequential activation of cell assemblies. Furthermore, we help to show how altered intrastriatal GABAergic signaling may produce aberrant network-level information processing in disorders such as Parkinson's and Huntington's diseases.Comment: 22 pages, 9 figure

Significance of Input Correlations in Striatal Function

The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia

In vivo Observation of the Release of Norepinephrine and In Vivo Optical Studies on the Direct and Indirect Paths of the Striatum

This thesis focuses on my work using optical techniques to study different brain regions in vivo. The ability to optically study neurons and the circuits they comprise in vivo is an important method to better understand their role in the healthy brain and their dysfunction in disease. The first part of my thesis focuses on my work using on a collaborative project using a new optical probe to study norepinephrine synapses in vivo. In this work we were able to observe the effects of amphetamine on norepinephrine release in vivo and observed some evidence of potential silent synapses. I also describe a new method of cranial window surgery I developed for optical imaging. This technique called PHASOR, is faster, and has a higher success rate, than traditional surgical methods. The improvements demonstrated in this new surgical technique may enable more widespread use of optical imaging methods. In the second part of my thesis, I used optical techniques to study the dorsal striatum in vivo in awake behaving mice. The direct and indirect paths of the dorsal striatum play an important role in motor behavior and motor learning. Dysfunction in these paths has been implicated in motor diseases as well as in mood disorders. In this thesis, I provide a review of the anatomy and physiology of the neurons that comprise the dorsal striatum, and the circuits that they form. The next chapters describe my work using optical techniques to record from these neurons in vivo. In my first set of experiments, I recorded from the direct and indirect paths during a behavioral task of anxiety and observed differential firing depending on the anxiety state of the mouse. Finally, in a preliminary set of experiments, I record from the direct and indirect paths during tasks of motor learning. I found that both paths show changes in firing during motor learning and that these changes differ between the dorsolateral and dorsomedial striatum

Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band

: Motor symptoms of Parkinson's Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the β range ([12-30] Hz). However, how dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here capture the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We highlight that both the loop between subthalamic nucleus (STN) and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe display resonances in the β range, and synchronize to a common β frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops are largely independent for high levels of dopamine, but progressively synchronize as dopamine is depleted due to the increased strength of the striatal loop. The model is validated against recent experimental reports on the role of cortical inputs, STN and GPe activity in the generation of β oscillations. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained β oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological β oscillations

Deep brain stimulation in the subthalamic nucleus for Parkinson's disease can restore dynamics of striatal networks

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson’s disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma and theta oscillations. These rhythms are at the heart of selection, initiation and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of the behavioral deficits observed in PD patients. Interrupting abnormal rhythms and restoring the interaction of rhythms as observed in the healthy striatum may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD, and how DBS can restore normal beta, gamma and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, that were recently shown to preferentially target fast spiking interneurons (FSI) in the striatum. We find that DBS in STN is able to normalize striatal medium spiny neuron (MSN) activity by recruiting FSI dynamics, and restoring the inhibitory potency of FSIs observed in normal condition. We also find that DBS allows the re-expression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study shows how BG connectivity can amplify beta oscillations, and delineates the role of DBS in disrupting beta oscillations and providing corrective input to STN efferents to restore healthy striatal dynamics. It also suggests how gamma oscillations can be leveraged to enhance or supplement DBS treatment and improve its effectiveness.https://doi.org/10.1101/2021.08.29.458121Published versio

Dynamics of dopamine signaling and network activity in the striatum during learning and motivated pursuit of goals

Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013.Cataloged from PDF version of thesis. "February 2013."Includes bibliographical references (p. 118-126).Learning to direct behaviors towards goals is a central function of all vertebrate nervous systems. Initial learning often involves an exploratory phase, in which actions are flexible and highly variable. With repeated successful experience, behaviors may be guided by cues in the environment that reliably predict the desired outcome, and eventually behaviors can be executed as crystallized action sequences, or "habits", which are relatively inflexible. Parallel circuits through the basal ganglia and their inputs from midbrain dopamine neurons are believed to make critical contributions to these phases of learning and behavioral execution. To explore the neural mechanisms underlying goal-directed learning and behavior, I have employed electrophysiological and electrochemical techniques to measure neural activity and dopamine release in networks of the striatum, the principle input nucleus of the basal ganglia as rats learned to pursue rewards in mazes. The electrophysiological recordings revealed training dependent dynamics in striatum local field potentials and coordinated neural firing that may differentially support both network rigidity and flexibility during pursuit of goals. Electrochemical measurements of real-time dopamine signaling during maze running revealed prolonged signaling changes that may contribute to motivating or guiding behavior. Pathological over or under-expression of these network states may contribute to symptoms experienced in a range of basal ganglia disorders, from Parkinson's disease to drug addiction.by Mark W. Howe.Ph.D.in Neuroscienc

The age of brain organoids : tailoring cell identity and functionality for normal brain development and disease modeling

Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases

The role of oscillation population activity in cortico-basal ganglia circuits.

The basal ganglia (BG) are a group of subcortical brain nuclei that are anatomically situated between the cortex and thalamus. Hitherto, models of basal ganglia function have been based solely on the anatomical connectivity and changes in the rate of neurons mediated by inhibitory and excitatory neurotransmitter interactions and modulated by dopamine. Depletion of striatal dopamine as occurs in Parkinson's Disease (PD) however, leads primarily to changes in the rhythmicity of basal ganglia neurons. The general aim of this thesis is to use frontal electrocorticogram (ECoG) and basal ganglia local field potential (LFP) recordings in the rat to further investigate the putative role for oscillations and synchronisation in these structures in the healthy and dopamine depleted brain. In the awake animal, lesion of the SNc lead to a dramatic increase in the power and synchronisation of P-frequency band oscillations in the cortex and subthalamic nucleus (STN) compared to the sham lesioned animal. These results are highly similar to those in human patients and provide further evidence for a direct pathophysological role for p-frequency band oscillations in PD. In the healthy, anaesthetised animal, LFPs recorded in the STN, globus pallidus (GP) and substantia nigra pars reticulata (SNr) were all found to be coherent with the ECoG. A detailed analysis of the interdependence and direction of these activities during two different brain states, prominent slow wave activity (SWA) and global activation, lead to the hypothesis that there were state dependant changes in the dominance of the cortico-subthalamic and cortico-striatal pathways. Multiple LFP recordings in the striatum and GP provided further evidence for this hypothesis, as coherence between the ECoG and GP was found to be dependent on the striatum. Together these results suggest that oscillations and synchronisation may mediate information flow in cortico-basal ganglia networks in both health and disease