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

Some thalamocortical projections of the pulvinar-posterior system of the thalamus in the cat.

We report here that the pattern of loss of dopamine that occurs in the brains of adult mice carrying the autosomal recessive weaver gene is the consequence both of failed postnatal development of the dopamine- containing mesostriatal innervation and of the disappearance of the early forming dopamine-island system For these studies, we compared the contents of dopamine extracted from 3 divisions of the striatum, the caudoputamen, nucleus accumbens, and olfactory tubercle, and from the midbrain of weaver and control littermate pups Catecholamines were extracted from tissues dissected from serial brain slices and were separated and measured using high-performance liquid chromatography followed by electrochemical detection The anatomical pattern formed by the catecholamine-containing innervation of the developing striatum was studied in 8-, 11-, 20-d-old, and 15-month-old weaver and control mice using tyrosine hydroxylase immunohistochemistry In weaver neonates (7- 8 d old), the dopamine-containing innervation of the caudoputamen is characterized by near-normal concentrations of dopamine and by a normal anatomical arrangement of dopamine islands Subsequently, however, the weaver disease is expressed in the caudoputamen as a failure of the dopamine islands to persist and of the dopamine-containing innervation of the matrix to develop at a normal rate Whereas the concentration of dopamine increases 44-fold between days 7 and 33 in normal animals, it increases only 16-fold in the weaver In spite of the severe reduction of dopamine, the weaver9s caudoputamen grows to near-normal size (85%)(ABSTRACT TRUNCATED AT 250 WORDS)

https://www.jneurosci.org/content/jneuro/7/8/2364.full.pdf

The postnatal development of the dopamine-containing innervation of dorsal and ventral striatum: effects of the weaver gene

Organization of the striate-recipient zone of the cat's lateralis posterior-pulvinar complex and its relations with the geniculostriate system

Dystonia is a disorder of motor programmes controlling semiautomatic movements or postures, with clinical features such as sensory trick, which suggests sensorimotor mismatch as the basis. Dystonia was originally classified as a basal ganglia disease. It is now regarded as a 'network' disorder including the cerebellum, but the exact pathogenesis being unknown. Rare autopsy studies have found pathology both in the striatum and the cerebellum, and functional disorganisation was reported in the somatosensory cortex in patients. Recent animal studies showed physiologically tight disynaptic connections between the cerebellum and the striatum. We review clinical evidence in light of this new functional interaction between the cerebellum and basal ganglia, and put forward a hypothesis that dystonia is a basal ganglia disorder that can be induced by aberrant afferent inputs from the cerebellum.

https://jnnp.bmj.com/content/jnnp/89/5/488.full.pdf

Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin?

In an earlier report we presented evidence pointing to a differential effect of the mutant gene weaver on the dopamine-containing fiber systems innervating the striatum. In mice homozygous for the weaver mutation, there is a severe loss of dopamine in the caudoputamen, the main target of the nigrostriatal system. By contrast, dopamine is entirely conserved in the nucleus accumbens, a target of the mesolimbic system, and is moderately affected in the olfactory tubercle. The present study shows that these defects in dopamine are gene dose-dependent, that they are established by the end of the first month of life, and that the losses are permanent and not progressive. As in homozygous weavers, the greatest defects in striatal dopamine in heterozygous weavers occur in the dorsolateral caudoputamen and the lateral olfactory tubercle. The abnormalities in the striatal dopamine content of weaver mice are not accompanied by abnormalities in the turnover of dopamine, judging from measurements of the dopamine metabolite dihydroxyphenylacetic acid. Norepinephrine content is also normal in each striatal region. No deficits in striatal dopamine occur in mice homozygous for the mutant genes staggerer and Purkinje cell degeneration, which, like the weaver mutation, result in ataxia and cerebellar pathology. A survey of nonstriatal regions in the weaver mice showed that the effects of the weaver gene on the dopamine-containing innervation of the forebrain are not confined to striatal targets but also extend to the septum and the hypothalamus. By contrast, dopamine in the frontal cortex, the amygdala, the olfactory bulb, and the retina is entirely spared. The pattern and extent of loss of dopamine in the weaver forebrain is thus region- and system-specific. In confirmation of our initial findings, a ca. 30% depletion of dopamine occurs in the weaver midbrain, the region containing the cell bodies of origin of the mesostriatal dopamine systems. A comparison of histofluorescent sections through weaver and control midbrains revealed a reduction of catecholamine-containing neurons in the pars compacta of the weaver animals. These results point to a subpopulation of dopamine-containing neurons as primary targets of the weaver gene or as being closely associated with such primary targets. As a gene-dose effect has also been shown for the cerebellar granule cell loss in the weaver, the mutant gene must have at least 2 cellular targets. We suggest that the cerebellar and mesostriatal pathologies may be linked by a common molecular mechanism.

https://www.jneurosci.org/content/jneuro/6/11/3319.full.pdf

Ann M. Graybiel

Papers

Some thalamocortical projections of the pulvinar-posterior system of the thalamus in the cat.

The postnatal development of the dopamine-containing innervation of dorsal and ventral striatum: effects of the weaver gene

Organization of the striate-recipient zone of the cat's lateralis posterior-pulvinar complex and its relations with the geniculostriate system

Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin?

Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions