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

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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

A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict

The expression of immediate-early genes of the fos/jun leucine zipper family can be regulated in striatal neurons by stimuli affecting the dopaminergic nigrostriatal system. The regulatory effects are gene specific, region specific, and striatal compartment specific. In the experiments reported here, we have explored the possibility that dopaminergic stimulation might also affect striatal expression of NGFI- A, a member of the zinc finger family of immediate-early genes. We treated healthy adult rats with amphetamine or cocaine and monitored the acute response of striatal neurons by in situ hybridization with oligonucleotide probes for NGFI-A mRNA. Both drugs evoked rapid, anatomically patterned increases in NGFI-A mRNA expression in the dorsal striatum (caudoputamen) and in the ventral striatum (nucleus accumbens, olfactory tubercle). The main response to each drug was in medium-sized neurons, known to be the projection neurons of the striatum. At every dose of amphetamine eliciting a response, the increased NGFI-A mRNA expression was preferentially concentrated in striosomes of the rostral caudoputamen, whereas cocaine at each dose given induced expression of NGFI-A mRNA in both striosomes and matrix at these striatal levels. The two indirect agonists evoked NGFI-A expression in both striatal compartments farther caudally, especially in the central and medial caudoputamen. Activation by both drugs was blocked by pretreatment with the D1-selective dopamine receptor antagonist SCH23390. These patterns of NGFI-A activation are remarkably similar to those found for Fos-like immunoreactivity following acute amphetamine and cocaine treatments, suggesting that coordinate activation of members of at least two immediate-early gene families occurs in the striatum following catecholaminergic stimulation. Such patterns of induction strongly support the view that the genomic responsiveness of the striosome and of the matrix compartments of the rostral striatum are distinct at the level of early-response gene expression. These findings raise the interesting possibility that some of the well-known effects of dopaminergic stimulation on neuropeptide and neurotransmitter expression in the striatum may reflect particular combinatorial patterns of immediate-early gene activation.

https://www.jneurosci.org/content/jneuro/12/7/2609.full.pdf

Dynamic regulation of NGFI-A (zif268, egr1) gene expression in the striatum

Anatomical organization of retinotectal afferents in the cat: An autodiographic study

The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost-benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi-electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making.

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Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making

Current understanding of basal ganglia function emphasizes their involvement in the focal, context-dependent release of motor and cognitive circuits in the brainstem and frontal lobes. How such selective action can arise despite the existence of massively convergent inputs from the cerebral cortex is unknown. However, anatomical work has suggested that specificity could be achieved in corticostriatal circuits by modular patterns of convergent and divergent cortical inputs to striatal projection neurons. To test for such modular activation of striatal neurons, we electrically microstimulated physiologically identified sites in the primary somatosensory (SI) and primary motor (MI) cortex of the squirrel monkey. We compared the efferent fiber distributions anterogradely traced from these sites to the distributions of striatal neurons activated by microstimulation to express Fos- and Jun B-like immediate-early gene proteins. We show that the microstimulation of sensorimotor cortex induces Fos and Jun B expression in localized cell clusters in the putamen and that these clusters match the anatomical input fiber clusters (matrisomes). The modular activation of striatal neurons by sensorimotor cortex seems likely. Unexpectedly, >75% of the Fos-positive nuclei in densely labeled cell clusters were in enkephalin-immunoreactive neurons. This expression pattern suggests that the primate sensorimotor cortex exerts a differential influence on the enkephalinergic (indirect pathway) as opposed to the substance P/dynorphin (direct pathway) projection neurons of the putamen. The densely labeled clusters of Fos-labeled enkephalinergic neurons occurred within larger zones containing sparsely distributed Fos-labeled parvalbumin neurons. Moreover, when the cortical stimulation induced expression of Fos-like protein only in sparsely distributed neurons, almost every putamenal neuron expressing Fos was a parvalbumin-containing (GABAergic) interneuron. These patterns suggest a model in which the primate sensorimotor cortex can target parvalbumin-containing inhibitory interneurons, which in turn depress the remaining neuronal activity within and around matrisomes in a feed-forward manner until sufficient coherent cortical input can overcome the inhibition to influence selectively enkephalinergic projection neurons in the activated matrisomes. Tuning of cortical input by striatal interneurons thus may be an important mechanism by which broader anatomical connections are dynamically adjusted to achieve selective flow of information through the basal ganglia.

https://www.jneurosci.org/content/jneuro/17/7/2477.full.pdf

Cortically driven immediate-early gene expression reflects modular influence of sensorimotor cortex on identified striatal neurons in the squirrel monkey.

Ann M. Graybiel

Papers

A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict

Dynamic regulation of NGFI-A (zif268, egr1) gene expression in the striatum

Anatomical organization of retinotectal afferents in the cat: An autodiographic study

Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making

Cortically driven immediate-early gene expression reflects modular influence of sensorimotor cortex on identified striatal neurons in the squirrel monkey.