Staging of brain pathology related to sporadic Parkinson’s disease

The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.

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A Neural Substrate of Prediction and Reward

Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in our concepts of the structural and functional organization of these nuclei. From earlier data it had appeared that the basal ganglia served primarily to integrate diverse inputs from the entire cerebral cortex and to "funnel" these influences, via the ventrolateral thalamus, to the motor cortex (Allen & Tsukahara 1974, Evarts & Thach 1969, Kemp & Powell 1971). In particular, the basal

/pdf/parallel-organization-of-functionally-segregated-circuits-159qr6wgp1.pdf

Parallel Organization of Functionally Segregated Circuits Linking Basal Ganglia and Cortex

Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.

The organization of the human cerebral cortex estimated by intrinsic functional connectivity

Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.

https://science.sciencemag.org/content/sci/255/5052/1707.full.pdf

Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system

The striatum is composed principally of GABAergic, medium spiny striatal projection neurons (MSNs) that can be categorized based on their gene expression, electrophysiological profiles, and input–output circuits. Major subdivisions of MSN populations include (1) those in ventromedial and dorsolateral striatal regions, (2) those giving rise to the direct and indirect pathways, and (3) those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input–output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia, and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology in these disorders.

/pdf/basal-ganglia-disorders-associated-with-imbalances-in-the-3jaelwivg8.pdf

Basal Ganglia Disorders Associated with Imbalances in the Striatal Striosome and Matrix Compartments

The striatum is important in basal ganglia motor control and movement disorders. In this study we demonstrate the existence of two distinct sensorimotor cortical input systems to the striatum of the squirrel monkey. The first is a group of discrete zones in the extrastriosomal matrix of the putamen ("matrisomes") that receive somatotopically organized projections from both the body map in ipsilateral primary motor cortex (MI) and maps in ipsilateral primary somatosensory cortex (SI). The second system is a group of matrisomes in largely different locations that receive somatotopically organized inputs from contralateral MI but not SI. Intracortical microstimulation and multiunit recording were used to guide deposits of multiple anterograde tracers in MI and SI. Striosome/matrix architecture was demonstrated by enkephalin immunohistochemistry. We found that inputs from regions of ipsilateral MI and SI that represented the same body parts sent projections to the same matrisomes of the ipsilateral putamen. Contralateral MI sent its strongest inputs to matrisomes that tended to interdigitate with those receiving inputs from ipsilateral SI and MI, except the contralateral MI face region, which sent projections that overlapped those from the ipsilateral MI face region. MI regions representing axial body parts (trunk and face) sent stronger representations to the contralateral putamen than did those representing distal parts (hand and foot). SI sent no contralateral projection. Thus, with the exception of the face representation, inputs from contralateral and ipsilateral body representations may alternate in the primate striatal matrix, an arrangement reminiscent of the alternating ocular dominance columns in visual cortex. Ipsilateral SI and MI and contralateral MI all innervated matrisomes intermingled with striosomes and with matrisomes not receiving sensorimotor cortical input. The patchiness of these maps is thus unlike the smoother somatotopic maps of sensorimotor cortex, and is also unlike the fractured somatotopy reported for the cerebellum.

https://www.jneurosci.org/content/jneuro/13/3/1120.full.pdf

Two input systems for body representations in the primate striatal matrix: experimental evidence in the squirrel monkey

Parietotectal projections were studied in the macaque monkey in experiments designed to compare the distribution of fibers originating in two cytoarchitecturally distinct regions within the inferior parietal lobule: the inferior bank of the intraparietal sulcus (area POa of Seltzer and Pandya, '80) and the adjoining part of area PG (von Bonin and Bailey, '47) on the convexity of the hemisphere, here called PGc. A dense fiber projection from POa to the intermediate and deep layers of the superior colliculus was observed by both anterograde autoradiographic and anterograde horseradish peroxidase methods. In contrast, only faint labeling was seen in the superior colliculus following injections of tritiated amino acids into area PGc on the convexity. In a second set of experiments, injections of horseradish peroxidase were placed in the intermediate and deep layers of the superior colliculus so that the cells of origin of the parietotectal projections could be identified. Many retrogradely labeled neurons were observed in POa, whereas very few labeled neurons were present in any other subdivision of the inferior parietal lobule or in the superior parietal lobule. These findings demonstrate that area POa has a prominent direct efferent projection to a major premotor region of the brainstem oculomotor system and suggest that by virtue of its parietotectal connection, this sulcal subdivision may have functional properties not shared with other subdivisions of the inferior parietal lobule.

The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus.

Organization of the nigrotectal connection: an experimental tracer study in the cat.

Understanding how an animal's ability to learn relates to neural activity or is altered by lesions, different attentional states, pharmacological interventions, or genetic manipulations are central questions in neuroscience. Although learning is a dynamic process, current analyses do not use dynamic estimation methods, require many trials across many animals to establish the occurrence of learning, and provide no consensus as how best to identify when learning has occurred. We develop a state-space model paradigm to characterize learning as the probability of a correct response as a function of trial number (learning curve). We compute the learning curve and its confidence intervals using a state-space smoothing algorithm and define the learning trial as the first trial on which there is reasonable certainty (>0.95) that a subject performs better than chance for the balance of the experiment. For a range of simulated learning experiments, the smoothing algorithm estimated learning curves with smaller mean integrated squared error and identified the learning trials with greater reliability than commonly used methods. The smoothing algorithm tracked easily the rapid learning of a monkey during a single session of an association learning experiment and identified learning 2 to 4 d earlier than accepted criteria for a rat in a 47 d procedural learning experiment. Our state-space paradigm estimates learning curves for single animals, gives a precise definition of learning, and suggests a coherent statistical framework for the design and analysis of learning experiments that could reduce the number of animals and trials per animal that these studies require.

/pdf/dynamic-analysis-of-learning-in-behavioral-experiments-4yy7to48lz.pdf

Ann M. Graybiel

Papers

Basal Ganglia Disorders Associated with Imbalances in the Striatal Striosome and Matrix Compartments

Two input systems for body representations in the primate striatal matrix: experimental evidence in the squirrel monkey

The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus.

Organization of the nigrotectal connection: an experimental tracer study in the cat.

Dynamic analysis of learning in behavioral experiments.